Extracellular matrix and traumatic brain injury.

The brain extracellular matrix (ECM) plays a crucial role in both the developing and adult brain by providing structural support and mediating cell-cell interactions. In this review, we focus on the major constituents of the ECM and how they function in both normal and injured brain, and summarize the changes in the composition of the ECM as well as how these changes either promote or inhibit recovery of function following traumatic brain injury (TBI). Modulation of ECM composition to facilitates neuronal survival, regeneration and axonal outgrowth is a potential therapeutic target for TBI treatment.

Curcumin restores diabetes induced neurochemical changes in the brain stem of Wistar rats.

Diabetes mellitus, when poorly controlled, leads to debilitating central nervous system (CNS) complications including cognitive deficits, somatosensory and motor dysfunction. The present study investigated curcumin's potential in modulating diabetes induced neurochemical changes in brainstem. Expression analysis of cholinergic, insulin receptor and GLUT-3 in the brainstem of streptozotocin (STZ) induced diabetic rats were studied. Radioreceptor binding assays, gene expression studies and immunohistochemical analysis were done in the brainstem of male Wistar rats. Our result showed that Bmax of total muscarinic and muscarinic M3 receptors were increased and muscarinic M1 receptor was decreased in diabetic rats compared to control. mRNA level of muscarinic M3, α7-nicotinic acetylcholine, insulin receptors, acetylcholine esterase, choline acetyltransferase and GLUT-3 significantly increased and M1 receptor decreased in the brainstem of diabetic rats. Curcumin and insulin treatment restored the alterations and maintained all parameters to near control. The results show that diabetes is associated with significant reduction in brainstem function coupled with altered cholinergic, insulin receptor and GLUT-3 gene expression. The present study indicates beneficial effect of curcumin in diabetic rats by regulating the cholinergic, insulin receptor and GLUT-3 in the brainstem similar to the responses obtained with insulin therapy.

ß2-adrenoceptor and insulin receptor expression in the skeletal muscle of streptozotocin induced diabetic rats: antagonism by vitamin D3 and curcumin.

Diabetes mellitus is a heterogeneous disease and nutritional therapy forms a necessary dimension for its long-term management. Traditional medicinal plants and vitamins are the potentially useful natural products for diabetes control. Diabetes causes atrophy and wasting of skeletal muscles resulting in major peripheral damage. The current study was designed to investigate the therapeutic effect of vitamin D3 and curcumin treatment on ß2-adrenoceptors, transcription factor CREB, insulin receptors, protein kinase B (Akt) and malate dehydrogenase activity in the skeletal muscle of diabetic rats. Radioreceptor binding assay was done for ß2-adrenoceptors using specific ligand, [³H] propranolol and gene expression studies of ß2-adrenoceptors, transcription factor CREB, insulin receptors and Akt were also done using specific probes. The results of the ß2-adrenoceptor assay showed significant increase in binding parameters, receptor number (B(max)) and equilibrium dissociation constant (K(d)) in the diabetic group in comparison to control. Similarly, an up regulation of ß2-adrenoceptor and CREB gene expression was observed in the diabetic group whereas the insulin receptor expression was down regulated which signifies the increased glycogenolysis, gluconeogenesis and decreased glycogenesis in the muscles. Expression of Akt was found to be up regulated in the diabetic group. Malate dehydrogenase activity was significantly decreased in both cytosolic and mitochondrial fractions of the diabetic group. All these molecular aspects were reversed to near control with vitamin D3 and curcumin treatment. Our results suggest the rising potential of both vitamin D3 and curcumin in the management of peripheral complications associated with diabetes.

Effect of vitamin D3 in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats.

Diabetes mellitus is a growing health problem worldwide and is associated with severe liver complications. The aim of the present study is to analyse the status of metabolic and free-radical-scavenging enzymes and second messengers in the liver of streptozotocin (STZ)-induced diabetic rats, and to determine the hepatoprotective role of vitamin D(3). All studies were performed using the liver of adult male Wistar rats. Gene expression studies were carried out using real-time PCR with specific probes. Second messenger levels were determined using (3)H-labelled Biotrak assay kits, and glucose uptake assay with D-[(14)C]glucose. The present results show that there was a decrease in hepatic glucose uptake, malate dehydrogenase activity, glycogen content, inositol triphosphate (IP(3)) and cyclic GMP levels, and superoxide dismutase, glutathione peroxidase, phospholipase C, cyclic AMP-responsive element-binding protein, vitamin D receptor (VDR) and insulin receptor (INSR) gene expression in the diabetic rats when compared with the controls (all P < 0·05), while cyclic AMP levels and GLUT2 expression were increased (P < 0·05). Treatment of the diabetic rats with vitamin D(3) and insulin reversed the altered parameters to near control values. In conclusion, the data suggest a novel role of vitamin D(3) in restoring impaired liver metabolism in STZ-induced diabetic rats by regulating glucose uptake, storage and metabolism. We demonstrated that the restoring effect of vitamin D(3) is mediated through VDR modulation, thereby improving signal transduction and controlling free radicals in the liver of diabetic rats. These data suggest a potential role for vitamin D(3) in the treatment of diabetes-associated hepatic complications.

Role of curcumin in the prevention of cholinergic mediated cortical dysfunctions in streptozotocin-induced diabetic rats.

Diabetes exacerbates neuronal injury mediated through neurotransmitters deregulation in cerebral cortex. Our study analyzed the neuroprotective effect of curcumin to prevent cortical dysfunction associated with diabetes. Our study revealed decreased gene expression of muscarinic M1, insulin receptor, SOD, choline acetyl transferase and increased gene expression of muscarinic M3, α7-nicotinic acetylcholine receptor, acetylcholine esterase and GLUT3 in cerebral cortex of diabetic rats. Curcumin and insulin treatment reversed this altered parameters to near control. Immunohistochemistry studies of muscarinic M1 and M3 confirmed the gene expression at protein level. Decreased novel arm entry of diabetic rats in Y-maze test, improved in treatment group. These results suggest that cholinergic dysfunction, impaired glucose transport and oxidative stress contributes to learning and memory deficits in diabetes and further suggest that antioxidant curcumin has potential therapeutic role in preventing and/or delaying the diabetic complications associated with brain.

Decreased GABA receptor binding in the cerebral cortex of insulin induced hypoglycemic and streptozotocin induced diabetic rats.

Hypoglycemia is the major problem to blood glucose homeostasis in treatment of diabetes and is associated with severe irreversible consequences including seizures, coma and death. GABAergic inhibitory function in the cerebral cortex plays an important role in controlling the excitability and responsiveness of cortical neurons. Present study analysed effects of insulin induced hypoglycemia and streptozotocin induced diabetes on the cortical GABA receptor binding, GABA(Aά1), GABA(B) receptor subtype expression, GAD and GLUT3 expression. Diabetic rats showed decreased [(3)H] GABA binding in the cerebral cortex compared to control while hypoglycemia exacerbated the decrease. GABA receptor subunits; GABA(Aά1), GABA(B) and GAD expression significantly decreased in diabetic rats whereas hypoglycemia significanly decreased the expression compared to diabetic. GLUT3 expression significantly up regulated during both hypo and hyperglycemia. Our results showed that hypoglycemia and hyperglycemia decreased GABAergic neuroprotective function in the cerebral cortex, which account for the increased vulnerability of cerebral cortex to subsequent neuronal damage during hypo/hyperglycemia.

Curcumin modulates dopaminergic receptor, CREB and phospholipase C gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats.

Curcumin, an active principle component in rhizome of Curcuma longa, has proved its merit for diabetes through its anti-oxidative and anti-inflammatory properties. This study aims at evaluating the effect of curcumin in modulating the altered dopaminergic receptors, CREB and phospholipase C in the cerebral cortex and cerebellum of STZ induced diabetic rats. Radioreceptor binding assays and gene expression was done in the cerebral cortex and cerebellum of male Wistar rats using specific ligands and probes. Total dopaminergic receptor binding parameter, B(max) showed an increase in cerebral cortex and decrease in the cerebellum of diabetic rats. Gene expression studies using real time PCR showed an increased expression of dopamine D1 and D2 receptor in the cerebral cortex of diabetic rats. In cerebellum dopamine D1 receptor was down regulated and D2 receptor showed an up regulation. Transcription factor CREB and phospholipase C showed a significant down regulation in cerebral cortex and cerebellum of diabetic rats. We report that curcumin supplementation reduces diabetes induced alteration of dopamine D1, D2 receptors, transcription factor CREB and phospholipase C to near control. Our results indicate that curcumin has a potential to regulate diabetes induced malfunctions of dopaminergic signalling, CREB and Phospholipase C expression in cerebral cortex and cerebellum and thereby improving the cognitive and emotional functions associated with these regions. Furthermore, in line with these studies an interaction between curcumin and dopaminergic receptors, CREB and phospholipase C is suggested, which attenuates the cortical and cerebellar dysfunction in diabetes. These results suggest that curcumin holds promise as an agent to prevent or treat CNS complications in diabetes.