Abstract
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-HT2A receptor subtype, gene expression studies on 5-HT2A, 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 Bmax and Kd showed a significant decrease (p < 0.001) whereas 5-HT2A 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-HT2A, 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, Bmax , Kd of 5-HT, 5-HT2A and gene expression of 5-HT2A, 5-HTT and INSR in hippocampus to near control. The gene expression of 5-HT2A 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.
Highlights
Diabetes is associated with several adverse effects on the brain, which results primarily from direct consequences of chronic hyperglycemia
Induction of Diabetes The animals were randomly divided into control (C), diabetic (D), insulin treated diabetic (D+I), diabetic treated with insulin + pyridoxine (DIP), diabetic treated with pyridoxine alone (D+P), diabetic treated with Aegle marmelose (D+A) and diabetic treated with Aegle marmelose + pyridoxine (DAP)
Treatment with pyridoxine alone and in combination with Aegle marmelose and insulin in diabetic rats was able to significantly reduce (p < 0.001) the increased blood glucose level to near the control value compared to diabetic group (Figure-1)
Summary
Diabetes is associated with several adverse effects on the brain, which results primarily from direct consequences of chronic hyperglycemia. Diabetes induces impairments in hippocampal synaptic plasticity, neurogenesis and associated cognitive deficits. Intrahippocampal insulin [1] or activation of insulin signalling pathways [2] block the effects of stress on learning and memory. Hippocampus dependent learning is correlated with a decrease in extracellular glucose, and intrahippocampal injection of glucose improves performance [3]. An ayurvedic medicinal tree, growing throughout the deciduous forest of India is reported to have antidiabetic effect in rats. L-tryptophan is converted to 5-HT in the presence of the co-enzyme pyridoxine [10]. Pyridoxine supplementation is used for cognitive impairment or dementia [12]
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