CLINICAL STUDIES ON THE FOLLOWING INGREDIENTS:
REGIONAL DISTRIBUTION OF γ‐AMINOBUTYRIC ACID (GABA) IN BRAIN OF THE RHESUS MONKEY*
—The concentrations of γ‐aminobutyric acid (GABA) in twenty different regions of Rhesus monkey brain were studied. The highest levels were found in the substantia nigra, globus pallidus, and hypothalamus. Regions of the cerebral cortex and thalamus contained low amounts and white matter the lowest. Indirect evidence supporting an inhibitory transmitter role for GABA is discussed.
Fahn, S., and L. J. Cote. “Regional distribution of γ‐aminobutyric acid (GABA) in brain of the rhesus monkey.” Journal of neurochemistry 15.3 (1968): 209-213.
SUSTAINED DRUG‐INDUCED ELEVATION OF BRAIN GABA IN THE RAT1
Abstract— The contents of GABA, homocarnosine, and β‐alanine can be raised in rat brain for long periods of time by the continued administration of phenelzine, aminooxyacetic acid (AOAA), or isonicotinic acid hydrazide (INH). These 3 compounds apparently act by preferential inhibition of the enzyme GABA aminotransferase (GABA‐T). Oral administration of phenelzine (20 mg/kg per day) caused a 25–50 percent increase in GABA levels in the rat brain but produced appreciable toxic side effects. A similar increase in GABA levels in the brain resulted from oral administration to rats of INH in a dosage of 60 mg/kg per day, without production of any obvious toxic effects. Simultaneous administration of large doses of pyridoxine did not abolish the GABA‐elevating effect of INH. Brain GABA levels in the rat were increased by approx. 50 percent by daily injections of AOAA (2.5 mg/kg per day). At this low dosage, AOAA injections in rats could be continued for at least 6 weeks without producing evident toxic effects. Oral administration of large amounts of GABA, on the other hand, failed to increase the content of GABA in the brains of rats not treated with GABA‐T inhibitors and failed to produce any further increase of brain GABA levels in rats treated with AOAA.
Perry, T. L., and Shirley Hansen. “SUSTAINED DRUG‐INDUCED ELEVATION OF BRAIN GABA IN THE RAT 1.” Journal of neurochemistry 21.5 (1973): 1167-1175.
Effect of Inhibitors of GABA Aminotransferase on the Metabolism of GABA in Brain Tissue and Synaptosomal Fractions
Abstract: Five inhibitors of the GABA degrading enzyme GABA‐aminotransferase (GABA‐T), viz., gabaculine, γ‐acetylenic GABA, γ‐vinyl GABA, ethanolamine O‐sulphate, and aminooxyacetic acid, as well as GABA itself and the antiepileptic sodium vdproate were administered to mice in doses equieffective to raise the electroconvulsive threshold by 30 V. The animals were killed at the time of maximal anticonvulsant effect of the respective drugs and GABA, GABA‐T and glutamate decarboxylase (GAD) were determined in whole brain and synaptosomes, respectively. The synaptosomal fraction was prepared from the brain by conventional ultracentrifugation procedures. All drugs studied brought about significant increases in both whole brain and synaptosomal GABA concentrations, and, except GABA itself, inhibited the activity of GABA‐T. Furthermore, all drugs, except GABA and γ‐acetylenic GABA, activated GAD in the synaptosomal fraction. This was most pronounced with ethanolamine O‐sulphate, which induced a twofold activation of this enzyme but exerted only a weak inhibitory effect on GABA‐T. The results suggest that activation of GAD is an important factor in the mechanism by which several inhibitors of GABA‐T and also valproate increase GABA concentrations in nerve terminals, at least in the relatively non‐toxic doses as used in this study.
Löscher, W. “Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions.” Journal of neurochemistry 36.4 (1981): 1521-1527.
The effect of intracerebroventricularly administered GABA on brain monoamine metabolism
Intracerebroventricular injection of γ-aminobutyric acid (GABA) was performed in male rats and the brain monoamines, 5-hydroxyindoleacetic acid (5-HIAA), tyrosine and tryptophan levels were measured. GABA induced within 30 min a marked dose-dependent increase in the brain contents of dopamine (DA), serotonin (5-HT), tyrosine and tryptophan, while noradrenaline (NA) was lowered. Large doses of GABA, i.e. 1.5–3 mg/rat, were required for these effects. Aminooxyacetic acid (AOAA), an inhibitor of GABA-transaminase, when given alone in a dose of 25 mg/kg i.p. caused a significant rise of DA, 5-HT, and tryptophan. The combination of GABA and AOAA raised these levels more than either agent alone. Picrotoxin (4 mg/kg, i.p.) a claimed GABA receptor antagonist partially counteracted the GABA-induced DA rise. Monoamine synthesis was studied in different parts of the brain by measuring the accumulated dopa and 5-hydroxytryptophan (5-HTP), 30 min after NSD 1015 (3-hydroxybenzylhydrazine HCl, 100 mg/kg) an inhibitor of aromatic L-aminoacid decarboxylase, given i.p. 5 min after GABA. GABA caused a marked rise in dopa formation both in DA-and NA-predominated brain regions. Also, the 5-HTP formation was enhanced. The effects on both dopa and 5-HTP formation showed marked regional differences. The data suggest that GABA, by activating specific receptors, causes inhibition of firing of dopaminergic neurons and the opposite effect on the noradrenergic neurons. The nature of the effect on 5-HT metabolism needs further investigation.
Biswas, Bratati, and Arvid Carlsson. “The effect of intracerebroventricularly administered GABA on brain monoamine metabolism.” Naunyn-Schmiedeberg’s archives of pharmacology 299.1 (1977): 41-46.
Effect of chronic caffeine administration oh monoamine and monoamine metabolite concentrations in rat brain
Caffeine was chronically administered in four doses (0, 10, 25, and 50 mg/kg/day) to rats via twice-daily intraperitoneal injections for 30 days. Concentrations of brain tissue monoamines, dopamine (DA), norepinephrine (NE), and serotonin (5HT), and monoamine metabolites, dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and 5-hydroxyindoleacetic acid (5HIAA), were determined. At the 10 mg/kg/day dose, no significant changes were found compared with controls. At 25 mg/kg/day and 50 mg/kg/day, significant changes were observed within each monoamine system. In the striatum, DA and 5HT were increased, while DOPAC was decreased. In frontal cortex, NE was increased. In the cerebellum, 5HT and MHPG were increased.
Kirch, D. G., et al. “Effect of chronic caffeine administration oh monoamine and monoamine metabolite concentrations in rat brain.” Neuropharmacology 29.6 (1990): 599-602.
Simultaneous Determination of Caffeine from Blood, Brain, and Muscle Using Microdialysis in an Awake Rat and the Effect of Caffeine on Rat Activity
The ability to deliver a formulation and to monitor a drug in an awake and freely moving rat is demonstrated using microdialysis probes in the jugular vein, brain striatum, and pectoral muscle. Caffeine, which is an important cytochrome P450 isozyme marker substrate, was employed as the model drug. Methods for successful determination of caffeine levels simultaneously through three microdialysis probes are described in detail. Delivery of the intraperitoneal dose without disturbing the rat and the ability to monitor the animal’s activity during the experiment are added enhancements for performing measurements in the awake animal.
Heppert, K., and M. Davies. “Simultaneous determination of caffeine from blood, brain, and muscle using microdialysis in an awake rat and the effect of caffeine on rat activity.” Current Separations 18.1 (1999): 3-8.
The Effect of Long Term Caffeine Treatment on Hypoxic-Ischemic Brain Damage in the Neonate
ABSTRACT: There is considerable concern over the widespread use of caffeine during and after pregnancy. We have therefore examined the effect of perinatal caffeine use on the vulnerability of the immature brain to hypoxic ischemia (HI). Rat pups were exposed to caffeine during the first 7 d after birth by addition of a low or a high dose (0.3 or 0.8 g/L) of caffeine to the drinking water of their dams. At 7 d the pups were exposed to unilateral carotid occlusion + exposure to 7.70% oxygen for 100 min. The extent of HI brain damage was evaluated 2 wk after the insult. The effects of caffeine on A1 and A2a receptors, A1 mRNA and A2a mRNA, were examined by receptor autoradiography and in situ hybridization. Caffeine, theobromine, theophylline, and paraxanthine were analyzed in plasma of separate animals. Exposure to caffeine reduced HI brain damage from 40.3 ± 3.2% in controls to 29.8 ± 4.0% (p < 0.05) in low dose and 33.7 ± 3.9% (NS) in the high dose group. The A1 receptor density measured as [3H]-l,3-dipropyl-8-cyclopentyl xanthine ([3H]-DPCPX) binding was not significantly affected after low dose caffeine but increased in the brain of rat pups in the high dose group. The A2a receptor density measured as [3H]-2[p-(2-carboxymethyl)-phenethylamino]-5′-N-ethylcarboxamidoadenosine ([3H]-CGS 21680) binding and the expression of A1 mRNA and A2a mRNA were not altered by caffeine treatment. In conclusion, low dose caffeine exposure (plasma levels corresponding to umbilical cord plasma in newborns of coffee-consuming mothers) reduced HI brain damage by 30% in 7-d-old rats. This ameliorating effect could not be accounted for by up-regulation of adenosine receptors.
Bona, Elsa, et al. “The effect of long term caffeine treatment on hypoxic-ischemic brain damage in the neonate.” Pediatric research 38.3 (1995): 312.
Bacopa Aerial Parts Extract
Antidiabetic and in Vivo Antioxidant Activity of Ethanolic Extract of Bacopa monnieri Linn. Aerial Parts: A Possible Mechanism of Action
Diabetes mellitus is a metabolic disorder affecting carbohydrate, fat and protein metabolism that affects nearly 10% of the population every year. The treatment of diabetes mellitus has been confined to use of oral hypoglycemic agents and insulin, the former being reported to possess serious side effects. This leads to an increasing demand for herbal products with an antidiabetic factor with little side effects. This article describes the antihyperglycaemic activity, in vivo antioxidant potential, the effect on glycosylation of hemoglobin and in-vitro peripheral utilization of glucose of the ethanolic extract of the aerial parts of Bacopa monnieri. The extract produced a significant decrease in the blood glucose level when compared with the controls in alloxan induced hyperglycemic rats both in the single dose as well as multiple dose experiments at the tested dose level and is comparable with the standard drug glibenclamide. It was observed that the ethanolic extract reversed the weight loss of the diabetic rats and they returned to near normal. The extract prevented significant elevation of glycosylated hemoglobin in vitro, with IC50 value being 11.25 µg/ml that is comparable with the reference drug?-tocopherol. Administration of the extract and glibenclamide significantly decreased the levels of TBARS, increased the content of GSH and increased the activity of SOD and CAT in the liver of diabetic rats. The extract increased peripheral glucose utilization in the diaphragm of diabetic rats in vitro, which is comparable with the action of insulin. Thus, the extract might have insulin-like activity and the antihyperglycemic effect of the extract might be due to an increase in peripheral glucose consumption as well as protection against oxidative damage in alloxanized diabetes.
Ghosh, Tirtha, et al. “Antidiabetic and in vivo antioxidant activity of ethanolic extract of Bacopa monnieri Linn. Aerial parts: a possible mechanism of action.” Iranian Journal of Pharmaceutical Research (2010): 61-68.
In Vitro Antioxidant and Hepatoprotective Activity of Ethanolic Extract of Bacopa monnieri Linn. Aerial Parts
The ethanol extract of Bacopa monnieri Linn. (Scrophulariaceae) aerial parts (EBM) was investigated for any in vitro and in vivo antioxidant and hepatoprotective effects. EBM was prepared and estimation of total phenolics was carried out. Further, the antioxidant activity of EBM was studied using four in vitro models. The number of total phenolics was estimated to be 47.7 (g of pyrocatechol equivalent per mg of extract. The reducing power of the extract was found to be concentration dependent. The antioxidant activity, nitric oxide scavenging activity, and superoxide radical scavenging activity was also concentration dependent with IC 50 value being 238.22 g/ml, 29.17 g/ml and 22.92 g/ml respectively. The activities were found to be comparable with the reference drugs. Different groups of animals (Wistar albino rats) were administered with paracetamol (500 mg/kg, p.o., once in a day for 7 days). EBM at the dose of 300 mg/kg/day and silymarin 25 mg/kg/day were administered to the paracetamol treated rats for seven days. The effects of EBM and silymarin on serum transaminases (SGOT, SGPT), alkaline phosphatase (ALP), bilirubin (Direct and Total), cholesterol (HDL and Total) and total protein were measured in the paracetamol-induced hepatotoxic rats. Further, the effects of the extract on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were estimated. EBM and silymarin produced significant (P < 0.05) hepatoprotective effect by decreasing the activity of serum enzymes, bilirubin, total cholesterol and in vivo lipid peroxidation and significantly (P < 0.05) increasing the levels of GSH, SOD, CAT, and HDL cholesterol. EBM also showed antioxidant effects on FeCl 2 -ascorbate-induced lipid peroxidation in rat liver homogenate. From these results, it was suggested that EBM could protect the liver cells from paracetamol-induced liver damage perhaps, by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from paracetamol.
Ghosh, Tirtha, et al. “In vitro antioxidant and hepatoprotective activity of ethanolic extract of Bacopa monnieri Linn. aerial parts.” Iranian Journal of Pharmacology and Therapeutics 6.1 (2007): 77-0.
Antimicrobial activity of various fractions of ethanol extract of Bacopa monnieri Linn. aerial parts
The ethyl acetate and n-butanol fractions of ethanol extract of Bacopa monnieri Linn. aerial parts were screened for antibacterial and antifungal activities by both zones of inhibition study and determination of minimum inhibitory concentration (MIC). The ethyl acetate fraction was found to be more potent than the n-butanol fraction, though both of them were endowed with antimicrobial activity. The present study reveals the potential usefulness of B. monnieri aerial parts in the treatment of various pathogenic diseases as mentioned in the Ayurvedic literature.
Ghosh, T., et al. “Antimicrobial activity of various fractions of ethanol extract of Bacopa monnieri Linn. aerial parts.” Indian Journal of Pharmaceutical Sciences 69.2 (2007): 312.
Phytotoxic and antimicrobial constituents of Bacopa monnieri and Holmskioldia sanguinea
The phytochemicals betulinic acid (1), wogonin (2) and oroxindin (3) isolated from the aerial parts of Bacopa monnieri and Holmskioldia sanguinea showed signiﬁcant antifungal activity against the two fungi Alternaria alternata and Fusarium fusiformis. Inhibition of root growth germination of wheat seeds was observed for all three compounds which showed 100% inhibition at 10 µg/mL. Compounds (1) and (2) showed potent inhibition of Alternaria alternata compared with oroxindin at a concentration of 4 µg/mL, whereas compound (2) was an effective inhibitor of both fungi. The structures of the compounds were established by spectral and chemical studies. Copyright © 2004 John Wiley & Sons, Ltd.
Chaudhuri, P. K., et al. “Phytotoxic and antimicrobial constituents of Bacopa monnieri and Holmskioldia sanguinea.” Phytotherapy Research: An International Journal Devoted to Pharmacological and Toxicological Evaluation of Natural Product Derivatives 18.2 (2004): 114-117.
Evaluation of the antitumor activity of stigmasterol, a constituent isolated from Bacopa monnieri Linn aerial parts against Ehrlich Ascites Carcinoma in mice
Cancer remains as one of the most common causes of mortality worldwide. Cancer chemoprevention by natural products is well accepted nowadays. Phytosterols are natural products, showing anticancer activity, besides other activities. The purpose of this study was to examine the antitumor and antioxidant activity of stigmasterol, a phytosterol isolated from aerial parts of Bacopa monnieri Linn. against Ehrlich Ascites Carcinoma (EAC) in Swiss albino mice. The effect of stigmasterol on the growth of a transplantable murine tumor, the life span of EAC bearing hosts, simultaneous alterations in the hematological profile, liver biochemical parameters (lipid peroxidation, antioxidant enzymes) and histopathological studies of the liver was examined. Stigmasterol decreased tumor volume, packed cell volume and viable cell count, and increased mean survival time thereby increasing the life span of EAC tumor-bearing mice. Hematological profile reverted to near normal levels in stigmasterol treated mice. Stigmasterol decreased the levels of lipid peroxidation and increased the levels of glutathione, superoxide dismutase and catalase in the liver of EAC bearing mice. Histopathological study of liver tissues showed that stigmasterol had a significant protective effect against EAC bearing mice, which corroborates the above findings. Lactate dehydrogenase (LDH) activity in ascitic fluid increased while membrane microviscosity of the EAC cells decreased upon stigmasterol treatment indicating its effect in the membrane integrity functions. The antitumor activity of stigmasterol might be mediated through the activation of protein phosphatase 2A by ceramide causing apoptosis, as is shown by structurally similar phytosterol.
Ghosh, Tirtha, Tapan Kumar Maity, and Jagadish Singh. “Evaluation of the antitumor activity of stigmasterol, a constituent isolated from Bacopa monnieri Linn aerial parts against Ehrlich Ascites Carcinoma in mice.” Oriental Pharmacy & Experimental Medicine 11.1 (2011): 41-49.
Bacosine isolated from aerial parts of Bacopa monnieri improves the neuronal dysfunction in Streptozotocin-induced diabetic neuropathy
Reactive oxygen species (ROS), the formation of advanced glycation end products (AGEs) and apoptosis are implicated in the pathogenesis of diabetic neuropathy. The aim of the present study was to explore the effect of Bacopa monnieri on thermal and mechanical hyperalgesia, allodynia, motor nerve conduction velocity (MNCV) and oxidative-nitrosative stress in Streptozotocin-induced experimental diabetes. Diabetic rats developed neuropathy which was evident from marked hyperalgesia and allodynia; reduced MNCV associated with increased formation of AGEs and ROS. Chronic treatment with B. monnieri alcohol extract (BA; 100, 200 and 400 mg/kg) and Bacosine (BS; 5 and 10 mg/kg) for 30 days starting from the 60th day of STZ-administration significantly attenuated behavioral and biochemical changes associated with diabetic neuropathy. The present study suggested that BA and BS corrected hyperglycemia and partially reversed the pain response in diabetic rats through modulation of oxidative-nitrosative stress and reduction in AGEs formation in the diabetic rats and thus it may find clinical application to treat neuropathic pain in diabetic patients.
Kishore, Lalit, Navpreet Kaur, and Randhir Singh. “Bacosine isolated from aerial parts of Bacopa monnieri improves the neuronal dysfunction in Streptozotocin-induced diabetic neuropathy.” Journal of functional foods 34 (2017): 237-247.
A Study on Antimicrobial Activity of Bacopa monnieri Linn. Aerial Parts
Objective: To study the antimicrobial activity of the ethanolic extract of aerial parts of Bacopa monnieri Linn. Materials and methods: Minimum inhibitory concentration of the extract was performed by broth dilution method and the zone of inhibition was studied by agar disc diffusion method at concentrations of 2, 5 and 10 mg/ml in DMSO. Ciprofloxacin (5 μg/ml) and Clotrimazole (25 μg/ml) were used as reference controls for the antibacterial and antifungal studies respectively. Results: The results of the MIC study revealed the antimicrobial activity of the extract against the tested strains of microorganisms between concentration ranges of 50 and 400 μg/ml. The results of the zone of inhibition study revealed concentration-dependent nature of the extract with better effectiveness against gram-positive bacteria than gram-negative bacteria. Conclusion: The present study indicates the potential usefulness of B. monnieri aerial parts in the treatment of various pathogenic diseases as mentioned in the Ayurvedic literature.
Ghosh, T., et al. “A study on antimicrobial activity of Bacopa monnieri Linn. aerial parts.” Journal of Natural Remedies 6.2 (2006): 170-173.
Effects of Soy Lecithin Phosphatidic Acid and Phosphatidylserine Complex (PAS) on the Endocrine and Psychological Responses to Mental Stress
Phosphatidylserine, derived from cow brains, has been shown previously to dampen the ACTH and cortisol response to physical stress. Further research investigated the influence of soy lecithin phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. In this study, we investigated the effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) supplementation on pituitary-adrenal reactivity (ACTH, cortisol) and on the psychological response (Spielberger State Anxiety Inventory stress subscale) to a mental and emotional stressor. Four groups of 20 subjects were treated for three weeks with daily dosages of either 400 mg PAS, 600 mg PAS, 800 mg PAS, or placebo before exposure to the Trier Social Stress Test (TSST). Treatment with 400 mg PAS resulted in a pronounced blunting of both serum ACTH and cortisol, and salivary cortisol responses to the TSST, but did not affect heart rate. The effect was not seen with larger doses of PAS. With regard to the psychological response, 400 mg PAS seemed to exert a specific positive effect on emotional responses to the TSST. While the placebo group showed the expected increase in distress after the test, the group treated with 400 mg PAS showed decreased distress. These data provide initial evidence for selective stress dampening the effect of PAS on the pituitary-adrenal axis, suggesting the potential of PAS in the treatment of stress-related disorders.
Reference: Hellhammer, J., et al. “Effects of soy lecithin phosphatidic acid and phosphatidylserine complex (PAS) on the endocrine and psychological responses to mental stress.” Stress 7.2 (2004): 119-126. DOI:10.1080/10253890410001728379
In vivo and in vitro modulation of central type benzodiazepine receptors by phosphatidylserine
The in vivo and in vitro modulation of central benzodiazepine binding sites (BDZ-R) by phosphatidylserine purified from the bovine cerebral cortex (BC-PS) was studied. Five days i.p. administration of 15 mg/kg/day of BC-PS liposomes increased the maximal number of binding sites (Bmax) for [3H]flunitrazepam in cerebral cortical membranes. In contrast, the density of hippocampal benzodiazepine recognition binding sites decreased. In cerebellar membranes, BC-PS treatment did not alter the characteristics of [3H] flunitrazepam binding. Similar experiments using phosphatidylcholine extracted from bovine brain (BC-PC) resulted in no changes in the [3H] flunitrazepam binding in the 3 neural structures studied. Confirming previous results, rats submitted to acute swimming stress showed a decrease in the density of cerebral cortex BDZ-R. Animals treated with BC-PS liposomes before stress showed cortical [3H] flunitrazepam binding significantly below treated, unstressed animals but not below controls. The effects of BC-PS liposomes appeared to be selective for the central type of BDZ-R since no changes were observed in [3H]RO 5-4864 binding, a radioligand specific for the peripheral type BDZ-R. Preincubation of cerebral cortical and cerebellar synaptosomal membranes with BC-PS liposomes (1–300 μg per assay) significantly increased in a concentration-dependent manner (up to 100 μg) the [3H] flunitrazepam binding. Scatchard analysis revealed changes in the apparent affinity without alterations in the Bmax. Very similar results were obtained using a purified PS from the spinal cord. BC-PC, phosphatidylinositol, phosphatidic acid and the lyso derivatives of PS and PC (lysoPS and lysoPC) were found to be ineffective. The facilitating effects of BC-PS and γ-aminobutyric acid (GABA) on [3H] flunitrazepam binding were not additive. As with BC-PS, the diglyceride cardiolipin added to cerebral cortical and cerebellar membranes induced a concentration-dependent (up to 25 μg) increase in [3H] flunitrazepam binding. Higher concentrations of cardiolipin produced a decrease of [3H] flunitrazepam binding. These results indicate that the central type benzodiazepine receptors are under the modulatory action of PS and suggest that this endogenous phospholipid may play a regulatory role on the benzodiazepine/GABA receptor function.
Reference: de Stein, Miguelina Levi, Jorge H. Medina, and Eduardo De Robertis. “In vivo and in vitro modulation of central type benzodiazepine receptors by phosphatidylserine.” Molecular Brain Research 5.1 (1989): 9-15.doi:10.1016/0169-328X(89)90012-0
Subunit identification and reconstitution of the N-type Ca2+ channel complex purified from brain
Calcium channels play an important role in regulating various neuronal processes, including synaptic transmission and cellular plasticity. The N-type calcium channels, which are sensitive to omega-conotoxin, are involved in the control of transmitter release from neurons. A functional N-type calcium channel complex was purified from rabbit brain. The channel consists of a 230-kilodalton subunit (alpha 1B) that is tightly associated with a 160-kilodalton subunit (alpha 2 delta), a 57-kilodalton subunit (beta 3), and a 95-kilodalton glycoprotein subunit. The complex formed a functional calcium channel with the same pharmacological properties and conductance as those of the native omega-conotoxin-sensitive calcium channel in neurons.
Reference: Sakai, Masashi, Hideyuki Yamatoya, and Satoshi Kudo. “Pharmacological effects of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents.” Journal of nutritional science and vitaminology 42.1 (1996): 47-54.DOI: 10.1126/science.8392754
Pharmacological Effects of Phosphatidylserine Enzymatically Synthesized from Soybean Lecithin on Brain Functions in Rodents
Soybean transphosphatidylated phosphatidylserine (SBtPS) was prepared from soybean phosphatidylcholine by transphosphatidylation using phospholipase D, and the fatty acids composition and pharmacological properties were compared with those of bovine brain cortex-derived phosphatidylserine (BC-PS) which was reported to improve cognitive disorders of senile dementia patients by oral administration (300mg/day). The molecular species of SB-tPS are rich in linoleic and palmitic acids whereas those of BC-PS are stearic and oleic acids. Despite the differences in fatty acid composition, SB-tPS displayed significant activities on the increase in brain glucose concentrations in mice (79mg/kg, i.v.) and the restoration of scopolamine-induced amnesia in rats (60mg/kg, i.p.) as did BC-PS. These results suggest the possibility that SB-tPS may prevent and/or improve senile dementia by oral administration.
Reference: Sakai, Masashi, Hideyuki Yamatoya, and Satoshi Kudo. “Pharmacological effects of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents.” Journal of nutritional science and vitaminology 42.1 (1996): 47-54.doi.org/10.3177/jnsv.42.47
PHARMACOLOGICAL EFFECTS OF PHOSPHATIDYLSERINE LIPOSOMES: THE ROLE OF LYSOPHOSPHATIDYLSERINE
Unique among the phospholipids, phosphatidylserine depresses brain energy metabolism when injected intravenously into mice in the form of sonicated liposomes. The possibility that this effect results from a metabolic transformation of phosphatidylserine is examined in this paper.
A strong enhancement of the phosphatidylserine effect is induced by the incubation of liposomes with rat serum. Similar phosphatidylserine activation is observed after the incubation of the phospholipid with purified phospholipase A2 from the pancreas. In both cases, phosphatidylserine is split into the deacylated derivative, lysophosphatidylserine.
Lysophosphatidylserine reproduces with greater efficacy the effect of phosphatidylserine on brain energy metabolism. Other lysophospholipids are not effective.
It is concluded that the pharmacological effects of phosphatidylserine liposomes are due to the generation of lysophosphatidylserine.
Reference: Bigon, E., et al. “Pharmacological effects of phosphatidylserine liposomes: the role of lysophosphatidylserine.” British journal of pharmacology 67.4 (1979): 611-616.DOI: 10.1111/j.1476-5381. 1979.tb08708.x
A REVIEW OF PHOSPHATIDYLSERINE PHARMACOLOGICAL AND CLINICAL EFFECTS. IS PHOSPHATIDYLSERINE A DRUG FOR THE AGEING BRAIN?
Reference: PEPEU, GIANCARLO, ILEANA MARCONCINI PEPEU, and LUIGI AMADUCCI. “A review of phosphatidylserine pharmacological and clinical effects. Is phosphatidylserine a drug for the aging brain?.” Pharmacological research 33.2 (1996): 73-80.doi:10.1006/phrs.1996.0013
Effects of chlorpromazine on phosphatidylserine biosynthesis in rat PUP brain exposed to ethanol in utero
Phosphatidylserine biosynthesis in rat pup brain was examined by assaying the serine base-exchange enzyme activity in the microsomal and plasma membrane fractions, and by measuring the incorporation of [3H] serine into phosphatidylserine in brain slices and in the intact brain. Chlorpromazine, either added in vitro into the incubation system or administered to animals via i.p. injection or feeding a liquid diet gave rise to an increase in the phosphatidylserine biosynthesis activity. Ethanol administered in the form of a liquid diet to pregnant rats (day 11-birth) resulted in a decrease in phosphatidylserine biosynthesis in the newborn and developing brain. The ethanol-induced decrease in phosphatidylserine biosynthetic activity could be reversed by adding chlorpromazine to the ethanol diet. Results demonstrate that phosphatidylserine biosynthesis in the neonatal brain is affected in opposite directions by chlorpromazine and ethanol. This poses the possibility that chlorpromazine administration may be effective in alleviating the deleterious effects caused by the decreased phosphatidylserine biosynthesis in the brain due to in utero ethanol exposure.
Reference: Rhodes, Philip G., Zhong-Yi Hu, and Grace Y. Sun. “Effects of chlorpromazine on phosphatidylserine biosynthesis in rat pup brain exposed to ethanol in utero.” Neurochemistry international 22.1 (1993): 75-80.doi:10.1016/0197-0186(93)90071-C
Age-dependent spontaneous EEG bursts in rats: Effects of brain phosphatidylserine
During aging, male Sprague-Dawley rats display increasing frequency of bursts of seizure-like EEG patterns. They also have a decreased retention of passive avoidance response and a loss of spontaneous alternation in a Y maze. A study was made on the effects of chronic administration of phosphatidylserine in aged rats. It was found that BC-PS reduced by 65% the number of seizures, and by 70% their duration. It also facilitated retention of passive avoidance and of spontaneous alternation behavior. These results suggest that phosphatidylserine can affect electrophysiological and behavioral parameters in aged rats probably by counteracting age-related biochemical changes.
Reference: Aporti, Ferrante, et al. “Age-dependent spontaneous EEG bursts in rats: effects of brain phosphatidylserine.” Neurobiology of Aging 7.2 (1986): 115-120.doi:10.1016/0197-4580(86)90149-1
Effect of Docosahexaenoic Acid on the Synthesis of Phosphatidylserine in Rat Brain Microsomes and C6 Glioma Cells
Abstract: Docosahexaenoic acid (22:6n-3) is the major polyunsaturated fatty acid (PUFA) in the CNS and accumulates particularly in phosphatidylserine (PS). We have investigated the effect of the 22:6n-3 compositional status on the synthesis of PS. The fatty acid composition of brain microsomes from offspring of rats artificially reared on an n-3-deficient diet showed a dramatic reduction of 22:6n-3 content (1.7 ± 0.1%) when compared with control animals (15.0 ± 0.2%). The decrease was accompanied by an increase in docosapentaenoic acid (22:5n-6) content, which replaced the 22:6n-3 phospholipids with 22:5n-6 molecular species, as demonstrated using HPLC/electrospray mass spectrometry. The n-3 deficiency did not affect the total amount of polyunsaturated phospholipids in brain microsomes; however, it was associated with a decrease in the total polyunsaturated PS content and with increased levels of 1-stearoyl-2-docosapentanoyl (18:0/22:5n-6) species, particularly in phosphatidylcholine. Incorporation of [3H] serine into PS in rat brain microsomes from n-3-deficient animals was slightly but significantly less than that of the control animals. Similarly, C6 glioma cells cultured for 24 h in 22:6n-3-supplemented media (10–40 µM) showed a significant increase in the synthesis of [3H]PS when compared with unsupplemented cells. Our data show that neuronal and glial PS synthesis is sensitive to changes in the docosahexaenoate levels of phospholipids and suggest that 22:6n-3 may be a modulator of PS synthesis.
Reference: Garcia, Martha C., et al. “Effect of docosahexaenoic acid on the synthesis of phosphatidylserine in rat brain microsomes and C6 glioma cells.” Journal of neurochemistry 70.1 (1998): 24-30.DOI: 10.1046/j.1471-4159.1998. 70010024.x
The Role of Phosphatidylserine Decarboxylase in Brain Phospholipid Metabolism
Abstract: In the brain, phosphatidylethanolamine can be synthesized from free ethanolamine either by a pathway involving the formation of CDP-ethanolamine and its transfer to diglyceride or by base-exchange of ethanolamine with existing phospholipids. Although de novo synthesis from serine has also been demonstrated, the metabolic pathway involved is not known. The enzyme phosphatidylserine decarboxylase appears to be involved in the synthesis of much of the phosphatidylethanolamine in the liver, but the significance of this route in the brain has been challenged. Our in vitro studies demonstrate the existence of phosphatidylserine decarboxylase activity in rat brain and characterize some of its properties. This enzyme is localized in the mitochondrial fraction, whereas the enzymes involved in base-exchange and the cytidine pathway are localized to microsomal membranes. Parallel in vivo studies showed that after the intracranial injection of L-[G-3H] serine, the specific activity of phosphatidylserine was greater in the microsomal fractions than in the mitochondrial fraction, whereas the opposite was true for phosphatidylethanolamine. When L-[U-14C] serine and [13H] ethanolamine were simultaneously injected, the 14C/3H ratio in mitochondrial phosphatidylethanolamine was 10 times that in microsomal phosphatidylethanolamine. The results demonstrate that serine is incorporated into the base moiety of phosphatidylethanolamine primarily through the decarboxylation of phosphatidylserine in brain mitochondria. A minimal value of 7% for the contribution of phosphatidylserine decarboxylase to whole-brain phosphatidylethanolamine synthesis can be estimated from the in vivo data.
Reference: Butler, Madeline, and Pierre Morell. “The role of phosphatidylserine decarboxylase in brain phospholipid metabolism.” Journal of neurochemistry 41.5 (1983): 1445-1454.DOI: 10.1111/j.1471-4159. 1983.tb00844.x
Huperzine A improves cognitive deficits caused by chronic cerebral hypoperfusion in rats
The effects of (−)-huperzine A, a promising therapeutic agent for Alzheimer’s disease, on learning behavior and on alterations of the cholinergic system, the oxygen free radicals, and energy metabolites induced by permanent bilateral ligation of the common carotid arteries were investigated in rats. Daily oral administration of huperzine A produced a significant improvement of the deficit in the learning of the water maze task, beginning 28 days after ischemia, correlating to about 33–40% inhibition of acetylcholinesterase activity in cortex and hippocampus. Huperzine A significantly restored the decrease in choline acetyltransferase activity in hippocampus and significantly reduced the increases in superoxide dismutase, lipid peroxide, lactate and glucose to their normal levels. The present findings demonstrate that the improvement by huperzine A of the cognitive dysfunction in the late phase in chronically hypoperfused rats is due to its effects, not only on the cholinergic system but also on the oxygen free radical system and energy metabolism. Our results strongly suggest that huperzine A has therapeutic potential for the treatment of dementia caused by cholinergic dysfunction and/or decrease of cerebral blood flow.
Wang, Li Ming, Yi Fan Han, and Xi Can Tang. “Huperzine A improves cognitive deficits caused by chronic cerebral hypoperfusion in rats.” European journal of pharmacology 398.1 (2000): 65-72.
Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease
In recent years, the most common pharmacological treatment for Alzheimer’s disease (AD) has been acetylcholinesterase (AChE) inhibition. However, this single-target approach has limited effectiveness and there is evidence that a multitarget approach might be more effective. Huperzine A (HupA), a novel alkaloid isolated from a Chinese herb, has neuroprotective effects that go beyond the inhibition of AChE. Recent data have demonstrated that HupA can ameliorate the learning and memory deficiency in animal models and AD patients. Its potentially beneficial actions include modification of β-amyloid peptide processing, reduction of oxidative stress, neuronal protection against apoptosis, and regulation of the expression and secretion of nerve growth factor (NGF) and NGF signaling.
Zhang, Hai Yan, and Xi Can Tang. “Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease.” Trends in pharmacological sciences 27.12 (2006): 619-625.
Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion
Chronic cerebral hypoperfusion has been suggested to contribute to the progression of dementia. Inflammation and white matter lesion (WML) are involved in the pathologic process. This study investigated whether huperzine A, a natural acetylcholinesterase (AChE) inhibitor, has beneficial effects on long‐lasting inflammation as well as cognitive impairment in a rat model of cerebral hypoperfusion and how it plays these roles. Chronic cerebral hypoperfusion was induced by occlusion of bilateral common carotid arteries (two‐vessel occlusion; 2VO). Huperzine A was initially given 150 min after 2VO and daily for 3, 7, 14, and 28 days. Learning and memory dysfunction as tested by Morris water maze performance was observed in 2VO‐operated rats and was significantly improved by huperzine A treatment. WML and activation staining of immune cells were evaluated by Klüver‐Barrera (KB) and immunohistochemistry, respectively. Myelin damage and increased immunostains were found in the optic tract at all indicated days. Huperzine A treatment significantly ameliorated all these phenomena. Moreover, huperzine A also suppressed overexpression of the inflammatory factor tumor necrosis factor‐α (TNF‐α) and overphosphorylation of JNK and p38 mitogen‐activated protein kinases (MAPKs) in a cell model of chronic hypoxia. Preincubation with mecamylamine (MEC), a nicotinic acetylcholine receptor (nAChR) antagonist, for 30 min before hypoxia notably reversed the effects of huperzine A on TNF‐α production and MAPKs phosphorylation. In conclusion, delayed and chronic administration of huperzine A could protect against 2VO‐induced cognitive impairment, which might be related to its beneficial effects on WML, and the nAChR‐dependent cholinergic anti‐inflammation pathway plays an important role. © 2009 Wiley‐Liss, Inc.
Wang, Juan, Hai Yan Zhang, and Xi Can Tang. “Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion.” Journal of neuroscience research 88.4 (2010): 807-815.
Huperzine A protects isolated rat brain mitochondria against a β-amyloid peptide
Our previous work in cells and animals showed that mitochondria are involved in the neuroprotective effect of huperzine A (HupA). In this study, the effects of HupA on isolated rat brain mitochondria were investigated. In addition to inhibiting the Aβ25-35 (40 μM)-induced decrease in mitochondrial respiration, adenosine 5′-triphosphate (ATP) synthesis, enzyme activity, and transmembrane potential, HupA (0.01 or 0.1 μM) effectively prevented Aβ-induced mitochondrial swelling, reactive oxygen species increase, and cytochrome c release. More interestingly, administration of HupA to isolated mitochondria promoted the rate of ATP production and blocked mitochondrial swelling caused by normal osmosis. These results indicate that HupA protects mitochondria against Aβ at least in part by preserving membrane integrity and improving energy metabolism. These direct effects on mitochondria further extend the noncholinergic functions of HupA.
Gao, Xin, et al. “Huperzine A protects isolated rat brain mitochondria against the β-amyloid peptide.” Free Radical Biology and Medicine 46.11 (2009): 1454-1462.
Comparison of the effects of natural and synthetic huperzine-A on rat brain cholinergic function in vitro and in vivo
(−)-Huperzine-A has been shown to be a promising agent for the treatment of dementia of the Alzheimer type. This substance is rare in nature. We have been able to prepare a racemic mixture of (±)-huperzine-A in quantity. In the absence of a chiral synthetic procedure for (−)-huperzine-A, this study sought to determine whether the racemic mixture would yield an in vitro and in vivo pharmacological profile of activity similar to that of the natural compound. The synthetic racemic mixture (±)-huperzine-A was 3 times less potent than (−)-huperzine-A in vitro (IC50s of 3 × 10−7 M and 10−7 M, respectively) because the former consisted of a racemic mixture of the compound in which the (+)-huperzine component was considerably less potent (IC50 = 7 × 10−6M). A comparable magnitude of effect was also observed in studies conducted in vivo, in which, over a range of 0.1–2.0 mg/kg administered intraperitoneally (i.p.), both (−)-huperzine-A and (±)-huperzine-A exerted significant inhibition of acetylcholinesterase activity, in all brain regions tested (hippocampus, striatum, hypothalamus, and frontal cortex). This inhibition of acetylcholinesterase activity was inversely related to levels of acetylcholine measured in the hippocampus and followed the same time course of effect. (−)-Huperzine-A and (±)-huperzine-A were shown to be more potent than physostigmine as inhibitors of acetylcholinesterase in vitro (IC50 = 6 × 10−7M). Moreover, their inhibitory effect on acetylcholinesterase in vivo was of a longer duration (peak activity of 20 min for physostigmine versus 60 min for the huperzine variants), at the doses tested. Finally, no effect was exerted by either of the huperzine variants on choline acetyltransferase activity in cortex or hippocampus, over a wide range of doses tested (0.1–1.0 mg/kg, i.p.). These findings demonstrate that (±)- huperzine-A compares in its activity and biological effects with the natural product, (−)-huperzine-A, both in vitro and in vivo.
Xi-Can, Tang, et al. “Comparison of the effects of natural and synthetic huperzine-A on rat brain cholinergic function in vitro and in vivo.” Journal of Ethnopharmacology 44.3 (1994): 147-155.
Huperzine A attenuates cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia
The protective effects of huperzine A, a novel acetylcholinesterase inhibitor, on hypoxic-ischemic (HI) brain injury were investigated in neonatal rats. A unilateral HI brain injury was produced by the ligation of left common carotid artery followed by 1 h hypoxia with 7.7% oxygen in 7-day-old rat pups. After 5 weeks, HI brain injury in rat pups resulted in working memory impairments shown by increased escape latency in a water maze and reduced time spent in the target quadrant. The combination of common carotid artery ligation and exposure to a hypoxic environment caused the damage in the striatum, cortex, and hippocampus in the ipsilateral hemisphere, and the neuronal loss in the CA1 region. Huperzine A was administrated daily at the dose of 0.05 or 0.1 mg/kg i.p. for 5 weeks after HI injury. The significant protection against HI injury on behavior and neuropathology was produced by huperzine A at the dose of 0.1 mg/kg. These findings suggest that huperzine A might be beneficial in the treatment of hypoxic-ischemic encephalopathy in neonates.
Wang, Lai Shuan, et al. “Huperzine A attenuates cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia.” Brain Research 949.1-2 (2002): 162-170.
Niacin Suppresses the Mitogen-Activated Protein Kinase Pathway and Attenuates Brain Injury After Cardiac Arrest in Rats*
Single high dose and repeated low dose of niacin attenuated brain injury and improved neurological outcome after cardiac arrest in rats. Their therapeutic benefits were associated with suppressions of the phosphorylations of p38 and c-Jun N-terminal kinase/stress-activated protein kinase and the cleavage of caspase 3.
Kwon, Woon Yong, et al. “Niacin suppresses the mitogen-activated protein kinase pathway and attenuates brain injury after cardiac arrest in rats.” Critical care medicine 41.9 (2013): e223-e232.
Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover.
The n-3 essential fatty acid eicosapentaenoic acid (EPA) was added to the conventional antidepressant treatment of a treatment-resistant severely depressed and suicidal male patient with a seven-year history of unremitting depressive symptoms. The niacin skin flush test and cerebral magnetic resonance scanning were carried out at baseline and nine months later. The addition of ethyl-EPA led to a dramatic and sustained clinical improvement in all the symptoms of depression, including a cessation of previously unremitting severe suicidal ideation, within one month. Symptoms of social phobia also improved dramatically. During the nine-month period the volumetric niacin response increased by 30%, the relative concentration of cerebral phosphomonoesters increased by 53%, and the ratio of cerebral phosphomonoesters to phosphodiesters increased by 79%, indicating reduced neuronal phospholipid turnover. Registered difference images showed that the EPA treatment was accompanied by structural brain changes including, in particular, a reduction in the lateral ventricular volume.
Puri, B. K., et al. “Eicosapentaenoic acid in treatment-resistant depression associated with symptom remission, structural brain changes and reduced neuronal phospholipid turnover.” International journal of clinical practice 55.8 (2001): 560-563.
NIACIN AND NIACINAMIDE TRANSPORT IN THE CENTRAL NERVOUS SYSTEM. IN VIVO STUDIES
The concentration of niacinamide in plasma and CSF was 0.5 and 0.7 μm respectively. The mechanisms by which niacin and niacinamide, which are not synthesized in the brain, enter the brain, CSF and choroid plexus were investigated by injecting [14C]niacin or [14C]niacinamide intravenously and intraventricularly. [14C]Niacin or [14C]niacinamide, with or without unlabeled niacin or niacinamide, were infused intravenously at a constant rate into conscious rabbits. At 3 h, [14C]niacinamide, but not [14C]niacin, readily entered CSF, choroid plexus and brain. The addition of 4.1 mmol/kg niacinamide to the infusate markedly depressed the relative entry of [14C]niacinamide into choroid plexus and brain but not into CSF. After intraventricular injection, [14C]niacin was rapidly cleared from CSF and readily entered the brain and choroid plexus. The addition of unlabeled niacin to the intraventricular injectate decreased the clearance of [14C]niacin from CSF and the entry of [14C]niacin into choroid plexus and brain. Unlike niacin, carrier niacinamide (82 μmol) in the injectate did not depress the extremely rapid clearance of intraventricularly injected [14C]niacinamide from CSF but did decrease the entry of [14C]niacinamide into the brain. These results show that the control of entry and exit of niacinamide and niacin is the mechanism, at least in part, by which total niacin and NAD levels in brain cells are regulated. In the case of niacinamide which readily passes between CSF and plasma, the regulation of entry of niacinamide into brain cells by a high-affinity accumulation system is an integral part of the homeostatic system. In the case of niacin, penetration into CSF and the extracellular space of brain from plasma as well as regulation of entry into brain cells by a saturable accumulation system are two distinct parts of the homeostatic system. In vivo, niacin that enters the central nervous system is converted to the principal plasma vitamer, niacinamide, in its free or bound forms such as NAD.
Spector, Reynold. “Niacin and niacinamide transport in the central nervous system. In vivo studies.” Journal of neurochemistry 33.4 (1979): 895-904.
NIACIN AND NIACINAMIDE ACCUMULATION BY RABBIT BRAIN SLICES AND CHOROID PLEXUS IN VITRO
The transport into and release of14C‐labeled niacin and niacinamide from rabbit brain slices and isolated choroid plexuses were studied. In vitro, both brain slices and choroid plexus concentrated 14C by specific, energy‐dependent mechanisms when [14C]niacinamide was added to the incubation medium. The saturable accumulation velocities, which were linear for 30 min, depended, in part, on the incorporation of the [14C]niacinamide into NAD. The XT and Ymax for 14C accumulation with [14C]niacinamide in the medium by brain slices and choroid plexus were 0.80 μM and 1.45 μmolkg−1 (30 min)−1, and 0.23 μM and 18.6 μmol kg−1 (30 min)−1 respectively. In vitro, the choroid plexus, unlike brain slices, vigorously concentrated 14C by a separate, specific energy‐dependent process when 14C niacin was added to the incubation medium. The saturable accumulation velocity, which was linear for 30 min, depended completely on the metabolism of [14C]niacin. The KT and Ymax for14C accumulation by choroid plexus with [14C]niacin in the medium were 18.1 μM and 439 μmol kg−1 (30 min)−1 respectively. Whether preincubated in [14C]niacin or [14C]niacinamide, choroid plexus released predominantly [14C]niacinamide.
SPECTQR, REYNOLD, and PAUL KELLEY. “Niacin and niacinamide accumulation by rabbit brain slices and choroid plexus in vitro.” Journal of neurochemistry 33.1 (1979): 291-298.
Vitamin B6 (Pyridoxine HCl
Vitamin B6‐dependent seizures
A 131/2h-year-old child died with vitamin B6-dependent seizures in progress. Microscopic findings in brain included an abnormally sparse quantity of central myelinated fibers in the cerebral hemispheres. Glutamic acid concentrations were elevated and GABA concentrations reduced in the frontal and occipital cortices but not in the spinal cord. All other amino acid concentrations were normal, except for increased cystathionine in the occipital cortex. Pyridoxal-5-phosphate (PLP) was reduced in the frontal cortex. Glutamic acid decarboxylase activity comparable to that of controls was detected when the PLP concentration was greater than 0.05 mM. These findings suggest that pyridoxine-dependent seizures in man are associated with reduced GABA concentrations in the brain and with diminished central white matter structures.
LOTT, IRA T., et al. “Vitamin B6‐dependent seizures: pathology and chemical findings in brain.” Neurology 28.1 (1978): 47-47.
Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial
The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer’s disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer’s disease, trials are needed to see if the same treatment will delay the development of Alzheimer’s disease.
Smith, A. David, et al. “Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial.” PloS one 5.9 (2010): e12244.
Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by folate, vitamin B6 and B12-deficient diet
Epidemiological and clinical studies indicate that elevated circulating level of homocysteine (Hcy) is a risk factor for developing Alzheimer’s disease (AD). Dietary deficiency of folate, vitamin B6 and B12 results in a significant increase of Hcy levels, a condition also known as hyperhomocysteinemia (HHcy).
In the present study, we tested the hypothesis that a diet deficient for these three important factors when administered to a mouse model of AD, i.e. Tg2576, will result in HHcy and in an acceleration of their amyloidotic phenotype.
Compared with Tg2576 mice on regular chow, the ones receiving the diet deficient for folate, B6 and B12 developed HHcy. This condition was associated with a significant increase in Aβ levels in the cortex and hippocampus and an elevation of Aβ deposits in the same regions. No significant changes were observed for steady-state levels of total APP, BACE-1, ADAM-10, PS1, and nicastrin in the brains of mice with HHcy. No differences were observed for the main Aβ catabolic pathways, i.e. IDE and neprilysin proteins, or the Aβ chaperone apolipoprotein E.
Our findings demonstrate that a dietary condition which leads to HHcy may also result in increased Aβ levels and deposition in a transgenic mouse model of AD-like amyloidosis. They further support the concept that dietary factors can contribute to the development of AD neuropathology.
Zhuo, Jia-Min, and Domenico Praticò. “Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by folate, vitamin B6 and B12-deficient diet.” Experimental gerontology 45.3 (2010): 195-201.
SOME EFFECTS OF DIETARY VITAMIN B6 DEFICIENCY AND 4‐DEOXYPYRIDOXINE ON γ‐AMINOBUTYRIC ACID METABOLISM IN RAT BRAIN
Investigations of the respective effects of dietary vitamin B6 deficiency and 4‐deoxypyridoxine (a vitamin B6 antagonist) on GABA metabolism in rat brain have been carried out. No convulsions were observed in rats subjected to either treatment. GABA levels were lowered by both treatments, the greatest diminutions being found with the dietary deficiency. Glutamic acid decarboxylase activity was reduced under both conditions, but the loss of activity in the B6 deficiency experiments could be attributed to cofactor depletion, whereas in the deoxypyridoxine experiments the loss of activity appears to be due to lower levels of available apoenzyme. The activity of GABA‐transaminase was not affected by deoxypyridoxine treatment and only moderately reduced in the B.5 deficient animals.
Bayoumi, R. A., J. R. Kirwan, and W. R. D. Smith. “Some effects of dietary vitamin B6 deficiency and 4‐deoxypyridoxine on γ‐aminobutyric acid metabolism in rat brain.” Journal of neurochemistry 19.3 (1972): 569-576.