Alteration in 5-HT2C, NMDA receptor and IP3 in cerebral cortex of epileptic rats: restorative role of Bacopa monnieri.

Bacopa monnieri is effective in stress management, brain function and a balanced mood. 5-HT2C receptors have been implicated in stress whereas NMDA receptors and mGlu5 play crucial role in memory and cognition. In the present study, we investigated the role of B. monnieri extract in ameliorating pilocarpine induced temporal lobe epilepsy through regulation of 5-HT2C and NMDA receptors in cerebral cortex. Our studies confirmed an increased 5-HT2C receptor function during epilepsy thereby facilitating IP3 release. We also observed an decreased NMDA receptor function with an elevated mGlu5 and GLAST gene expression in epileptic condition indicating the possibility for glutamate mediated excitotoxicity. These alterations lead to impaired behavioural functions as indicated by the Elevated Plus maze test. Carbamazepine and B. monnieri treatments to epileptic rats reversed the alterations in 5-HT2C, NMDA receptor functions and IP3 content thereby effectively managing the neurotransmitter balance in the cerebral cortex.

Striatal dopamine receptors modulate the expression of insulin receptor, IGF-1 and GLUT-3 in diabetic rats: effect of pyridoxine treatment.

The incidence of type 2 diabetes mellitus is rising at alarming proportions. Central nervous system plays an important part in orchestrating glucose metabolism, with accumulating evidence linking dysregulated central nervous system circuits to the failure of normal glucoregulatory mechanisms. Pyridoxine is a water soluble vitamin and it has important role in brain function. This study aims to evaluate the role of pyridoxine in striatal glucose regulation through dopaminergic receptor expressions in streptozotocin induced diabetic rats. Radio receptor binding assays for dopamine D(1), D(2) receptors were done using [(3)H] 7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol and [(3)H] 5-chloro-2-methoxy-4-methylamino-N-[-2-methyl-1-(phenylmethyl)pyrrolidin-3-yl]benzamide. Gene expressions were done using fluorescently labeled Taqman probes of dopamine D(1), D(2) receptor, Insulin receptor, Insulin like growth factor-1(IGF-1) and Glucose transporter-3 (GLUT-3). Bmax of dopamine D(1) receptor is decreased and B(max) of dopamine D(2) was increased in diabetic rats compared to control. Gene expression of dopamine D(1) receptor was down regulated and dopamine D(2) receptor was up regulated in diabetic rats. Our results showed decreased gene expression of Insulin receptor, IGF-1 and increased gene expression of GLUT-3 in diabetic rats compared to control. Pyridoxine treatment restored diabetes induced alterations in dopamine D(1), D(2) receptors, Insulin receptor, IGF-1, GLUT-3 gene expressions in striatum compared to diabetic rats. Insulin treatment reversed dopamine D(1), D(2) receptor, GLUT-3 mRNA expression, D(2) receptor binding parameters in the striatum compared to diabetic group. Our results suggest the potential role of pyridoxine supplementation in ameliorating diabetes mediated dysfunctions in striatal dopaminergic receptor expressions and insulin signaling. Thus pyridoxine has therapeutic significance in diabetes management.

Decreased GABA receptor in the cerebral cortex of epileptic rats: effect of Bacopa monnieri and Bacoside-A.

BACKGROUND: Gamma amino butyric acid (GABA), the principal inhibitory neurotransmitter in the cerebral cortex, maintains the inhibitory tones that counter balances neuronal excitation. When this balance is perturbed, seizures may ensue. METHODS: In the present study, alterations of the general GABA, GABAA and GABAB receptors in the cerebral cortex of the epileptic rat and the therapeutic application of Bacopa monnieri were investigated. RESULTS: Scatchard analysis of [3H]GABA, [3H]bicuculline and [3H]baclofen in the cerebral cortex of the epileptic rat showed significant decrease in Bmax (P < 0.001) compared to control. Real Time PCR amplification of GABA receptor subunits such as GABAAά1, GABAAγ, GABAAδ, GABAB and GAD where down regulated (P < 0.001) in epileptic rats. GABAAά5 subunit and Cyclic AMP responsible element binding protein were up regulated. Confocal imaging study confirmed the decreased GABA receptors in epileptic rats. Epileptic rats have deficit in radial arm and Y maze performance. CONCLUSIONS: Bacopa monnieri and Bacoside-A treatment reverses epilepsy associated changes to near control suggesting that decreased GABA receptors in the cerebral cortex have an important role in epileptic occurrence; Bacopa monnieri and Bacoside-A have therapeutic application in epilepsy management.

Alterations in hippocampal serotonergic and INSR function in streptozotocin induced diabetic rats exposed to stress: neuroprotective role of pyridoxine and Aegle marmelose.

Diabetes and stress stimulate hippocampal 5-HT synthesis, metabolism and release. The present study was carried out to find the effects of insulin, Aegle marmelose alone and in combination with pyridoxine on the hippocampal 5-HT, 5-HT(2A) receptor subtype, gene expression studies on 5-HT(2A), 5-HTT, INSR, immunohistochemical studies and elevated plus maze in streptozotocin induced diabetic rats. 5-HT content showed a significant decrease (p < 0.001) and a significant increase (p < 0.001) in 5-HIAA in hippocampus of diabetic rats compared to control. 5-HT receptor binding parameters B(max) and Kd showed a significant decrease (p < 0.001) whereas 5-HT(2A) receptor binding parameters Bmax showed a significant decrease (p < 0.001) with a significant increase (p < 0.05) in Kd in hippocampus of diabetic rats compared to control. Gene expression studies of 5-HT(2A), 5-HTT and INSR in hippocampus showed a significant down regulation (p < 0.001) in diabetic rats compared to control. Pyridoxine treated in combination with insulin and A. marmelose to diabetic rats reversed the 5-HT content, B(max), Kd of 5-HT, 5-HT(2A) and gene expression of 5-HT(2A), 5-HTT and INSR in hippocampus to near control. The gene expression of 5-HT(2A) and 5-HTT were confirmed by immunohistochemical studies. Behavioural studies using elevated plus maze showed that serotonin through its transporter significantly increased (p < 0.001) anxiety-related traits in diabetic rats which were corrected by combination therapy. Our results suggest that pyridoxine treated in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalising diabetic related stress and anxiety through hippocampal serotonergic function. This has clinical significance in the management of diabetes.

Down regulation of cerebellar serotonergic receptors in streptozotocin induced diabetic rats: Effect of pyridoxine and Aegle marmelose.

Oxidative stress plays an important role in cerebellar damage caused by diabetes, leading to deterioration in glucose homeostasis causing metabolic disorders. The present study was carried out to find the effects of Aegle marmelose leaf extract and insulin alone and in combination with pyridoxine on the cerebellar 5-HT through 5-HT(2A) receptor subtype, gene expression studies on the status of antioxidants-superoxide dismutase (SOD), glutathione peroxidase (GPx), 5-HT(2A) and 5-HT transporter (5-HTT) and immunohistochemical studies in streptozotocin induced diabetic rats. 5-HT and 5-HT(2A) receptor binding parameters, B(max) and K(d), showed a significant decrease (p<0.001) in the cerebellum of diabetic rats compared to control. Gene expression studies of SOD, GPx, 5-HT(2A) and 5-HTT in cerebellum showed a significant down regulation (p<0.001) in diabetic rats compared to control. Pyridoxine treated alone and in combination with insulin, A. marmelose to diabetic rats reversed the B(max), K(d) of 5-HT, 5-HT(2A) and the gene expression of SOD, GPx, 5-HT(2A) and 5-HTT in cerebellum to near control. The gene expression of 5-HT(2A) and 5-HTT were confirmed by immunohistochemical studies. Also, the Rotarod test confirms the motor dysfunction and recovery by treatment. These data suggest the antioxidant and neuroprotective role of pyridoxine and A. marmelose through the up regulation of 5-HT through 5-HT(2A) receptor in diabetic rats. Our results suggest that pyridoxine treated alone and in combination with insulin and A. marmelose has a role in the regulation of insulin synthesis and release, normalizing diabetic related oxidative stress and neurodegeneration affecting the motor ability of an individual by serotonergic receptors through 5-HT(2A) function. This has clinical significance in the management of diabetes.

Down-regulation of cerebellar 5-HT(2C) receptors in pilocarpine-induced epilepsy in rats: therapeutic role of Bacopa monnieri extract.

Epilepsy is a syndrome of episodic brain dysfunction characterized by recurrent unpredictable, spontaneous seizures. Cerebellar dysfunction is a recognized complication of temporal lobe epilepsy and it is associated with seizure generation, motor deficits and memory impairment. Serotonin is known to exert a modulatory action on cerebellar function through 5HT(2C) receptors. 5-HT(2C) receptors are novel targets for developing anti-convulsant drugs. In the present study, we investigated the changes in the 5-HT(2C) receptors binding and gene expression in the cerebellum of control, epileptic and Bacopa monnieri treated epileptic rats. There was a significant down regulation of the 5-HT content (p<0.001), 5-HT(2C) gene expression (p<0.001) and 5-HT(2C) receptor binding (p<0.001) with an increased affinity (p<0.001). Carbamazepine and B. monnieri treatments to epileptic rats reversed the down regulated 5-HT content (p<0.01), 5-HT(2C) receptor binding (p<0.001) and gene expression (p<0.01) to near control level. Also, the Rotarod test confirms the motor dysfunction and recovery by B. monnieri treatment. These data suggest the neuroprotective role of B. monnieri through the upregulation of 5-HT(2C) receptor in epileptic rats. This has clinical significance in the management of epilepsy.