In another study Yerra and Kumar used streptozotocin to
In another study, Yerra and Kumar (2016) used streptozotocin to induce diabetic neuropathy in rats. Mechanical/thermal hyperalgesia, motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF) were evaluated. In vitro studies of Neuro2a (N2A) cell culture were performed under a condition of high glucose for the analysis of mitochondrial dysfunction. Treatment for two weeks with a potent allosteric activator of AMPK (A769662) attenuated pain hypersensitivity, restored MNCV and SNCV, decreased ROS, malondialdehyde and glutathione (GSH) and induced higher levels of GSH, reversing oxidative stress. Treatment with A769662 of high glucose-exposed N2A Process Measures and peripheral nerves in STZ-induced rats reduced the number of positive cells on the TUNEL test as well as levels of inflammatory markers. Mitochondrial biogenesis and autophagy were also stimulated with the AMPK activator, demonstrating the beneficial effect of AMPK as a possible treatment for diabetic neuropathy. According to Yuan et al. (2013), resveratrol has a protective effect against the toxicity induced by ethanol on Schwann cells (SCs) in vitro, improving cell viability and reducing apoptosis. Resveratrol increased the mRNA and protein levels of BDNF and glial cell line-derived neurotrophic factor (GDNF) in the ethanol-treated SCs, possibly protecting these cells from ethanol-induced cell death. Moreover, when the SCs culture was subjected to specific inhibitors of AMPK (Compound C) and SIRT1 (nicotinamide), the beneficial effect of resveratrol was reversed, indicating that resveratrol may be exerting its neuroprotective effects through the AMPK-SIRT1 pathway. Huntington's disease is a hereditary, neurodegenerative disease associated with 36 or more CAG repeats in the huntingtin (Htt) gene. The major characteristic of Huntington's disease is neuronal loss in the striatum and cortex, which leads to movement disorders and dementia. According to Chou et al. (2005), transgenic Huntington's mice (R6/2) submitted to a daily administration with CGS21680 (CGS), which is an agonist selective for adenosine A2A receptor (A2A-R), induced a delay in the progressive deterioration of motor performance and prevented a reduction in brain weight. Treatment with CGS reduced levels of choline expression in the striatum, the size of the ubiquitin-positive neuronal intranuclear inclusions and mutant Htt aggregation. Moreover, chronic treatment with CGS diminished glucose levels and the overactivation of AMPK in the striatum of R6/2 mice. Since AMPK is crucial sensor of energetic metabolism, the beneficial effects of CGS may be correlated with the modulation of the energetic dysfunction caused by Htt mutation. Activation of the AMPKα1 isoform occurred in striatal neurons of humans and mice with Huntington's. R6/2 transgenic mice exhibit overactivation of AMPKα1 in the striatum and are characterized by brain atrophy, decreased brain weight, neuronal loss and an increased formation of Htt aggregates. Ju et al. (2011) found a higher nuclear accumulation of pAMPKα in the neurons of the nucleus striatum and cortex of Huntington's patients and R6/2 transgenic mice, whereas pAMPKα was found in the neuronal cytoplasm in non-Huntington's subjects and non-diseased mice. Treatment of transgenic animals with AICAR increased the neuropathological characteristics of Huntington's, such as enlargement of the ventricles followed by a progressive reduction in brain weight, increased pAMPKα and AMPKα1 expression, activated the caspase-3 protein and reduced Bcl-2 expression in the striatum. Moreover, Compound C greatly reduced the nuclear localization of AMPKα1 in R6/2 mice provoked by AICAR. In another study, Ju et al. (2014) found that elevated oxidative stress caused abnormal activation of AMPKα1 and subsequently induced neurotoxicity in a striatal progenitor cell line and the striatum of R6/2 transgenic mouse model, suggesting positive feedback between ROS and AMPKα1 in Huntington's striatal neurons. Chronic treatment with the antioxidant N-acetyl-cysteine suppressed the activation of AMPKα1, reduced neuronal toxicity and ventricle enlargement, increased neuronal density and improved motor dysfunction.