Decreased Cholinergic Receptor Expression in the Striatum: Motor Function Deficit in Hypoglycemic and Diabetic Rats

Abstract

Hypoglycemic brain injury is a common and serious complication of insulin therapy associated with diabetes. This study evaluated the effect of insulin-induced hypoglycemia and STZ-induced diabetes on striatal cholinergic receptors and enzyme expression and on motor function. Cholinergic enzymes: AChE and ChAT gene expression, radioreceptor binding assay and immunohistochemistry of muscarinic M1, M3 receptors and α7nAChR were carried out. Motor performance on grid walk test was analysed. AChE and ChAT expression significantly downregulated in hypoglycemic and diabetic rats. Total muscarinic and Muscarinic M3 receptor binding decreased in hypoglycemic rats compared to diabetic rats whereas muscarinic M1 receptor binding increased in hypoglycemic rats compared to diabetic rats. Real-time PCR analysis and confocal imaging of muscarinic M1, M3 receptors confirmed the changes in muscarinic receptor binding in hypoglycemic and diabetic rats. In hypoglycemic rats, α7nAChR expression significantly up regulated compared to diabetic rats. Grid walk test demonstrated the impairment in motor function and coordination in hypoglycemic and hyperglycemic rats. Neurochemical changes along with the behavioral data implicate a role for impaired striatal cholinergic receptor function inducing motor function deficit induced by hypo and hyperglycemia. Hypoglycemia exacerbated the neurobehavioral deficit in diabetes which has clinical significance in the treatment of diabetes.

Experimentally induced diabetes causes glial activation, glutamate toxicity and cellular damage leading to changes in motor function

“…Alterations in motor behavior following diabetes was previously well reported both in human and animal models with underlying causes of increased blood glucose level associated micro- or macrovascular complications (Demirbüken et al, 2012) and altered neurotransmission (Sherin et al, 2012). In our study, the diabetic animals were showing reduced falling latency on Rotarod and poor or weak muscular strength in grip strength meter indicating impaired motor/muscle activity upto the 12 weeks of diabetic duration.…”

Retinal Deficits Precede Cognitive and Motor Deficits in a Rat Model of Type II Diabetes

“…The rotarod (San Diego Instruments) was used to measure balance and motor coordination, which have been shown to be impaired in diabetic animals. 25,47 The rats were placed on a rotating bar, and the latency to fall was recorded. Prior to testing, the animals were allowed 1 minute to acclimate to the stationary rotarod.…”

“…Oxidative stress, hypoxia, lipid abnormalities, and inflammation occur in both the brain and retina with diabetes, suggesting that the disease is damaging both tissues via similar pathways. [18][19][20][21][22][23] Deficits in both cognitive and motor function have been shown to occur with diabetes, 24,25 and the presence of DR is associated with cognitive deficits and greater amounts of ischemia in the brain. 26 Early or nonproliferative DR (which may indicate chronic hyperglycemia) is associated with structural changes in brain as well as deficits in attention, concentration, and information processing.…”

Long Term Effects of Neonatal Hypoglycemia on Muscarinic Receptor Function in the Cerebellum

“…The gene expression of muscarinic M3 receptor subtype showed a significant decrease with alterations in the key metabolic enzymes in cholinergic pathway. Reduction in muscarinic receptors was reported under hypoglycaemic and hyperglycaemic situations, which contributes to defective insulin signalling, neurodegenerative and cardiovascular complications [18][19][20].…”