Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation

Abstract

Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662). A769662 (15 and 30 mg/kg, i.p) was administered to Sprague-Dawley rats (250-270 g) for 2 weeks after 6 weeks of streptozotocin (STZ) injection (55 mg/kg, i.p.). Behavioural parameters (mechanical/thermal hyperalgesia) and functional characteristics (motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF)) were assessed. For in vitro studies, Neuro2a (N2A) cells were incubated with 25 mM glucose to simulate high glucose condition and then studied for mitochondrial dysfunction and protein expression changes. STZ administration resulted in significant hyperglycaemia (>250 mg/dl) in rats. A769662 treatment significantly improved mechanical/thermal hyperalgesia threshold and enhanced MNCV, SNCV and NBF in diabetic animals. A769662 exposure normalised the mitochondrial superoxide production, membrane depolarisation and markedly increased neurite outgrowth of N2A cells. Further, AMPK activation also abolished the NF-κB-mediated neuroinflammation. A769662 treatment increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1α-directed mitochondrial biogenesis and autophagy induction. Our study supports that compromised AMPK signalling in hyperglycaemic conditions causes defective mitochondrial biogenesis ultimately leading to neuronal dysfunction and associated deficits in DN and activation of AMPK can be developed as an attractive therapeutic strategy for the management of DN.

Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy

“…Reduced vascular innervations to the peripheral nerves leads to endoneurial hypoxia, nerve ischemia, and loss of neurotrophic support which might have contributed to neuronal dysfunction as seen in both clinical and experimental DN [48]. Chronic hyperglycaemia associated with diabetes resulted in compromised conduction velocities and blood flow deficits in the diabetic rats in line with previous studies [2,14,15,24]. NF-jB is the principle transcription factor found to involve in the direct regulation of cyclooxygenase 2 (COX-2), inducible nitric oxide synthase (iNOS), and other inflammatory cytokines.…”

Resistin inhibits neuronal autophagy through Toll-like receptor 4

“…This promotes both hypothalamic and peripheral inflammation leading to the alteration of insulin, adiponectin and FGF21 signaling (Benomar et al 2016). Furthermore, it has been reported that neuroinflammation impairs autophagy (Bosch & Kichian 2015, Su et al 2016, Yerra & Kumar 2017, but the impact of resistin on autophagy was not yet investigated and remains unknown. Here, we used human neuroblastoma SH-SY5Y cell line as model to decipher the mechanism by which resistin could potentially affect neuronal autophagy.…”

Neuroinflammation contributes to autophagy flux blockage in the neurons of rostral ventrolateral medulla in stress-induced hypertension rats

“…Chronic inflammation, as seen in several lysosomal storage diseases, impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis [ 24 ]. It was reported that neuroinflammation and autophagy impairment led to neuronal dysfunction and associated deficits in hyperglycemia-induced neuronal injury in experimental models of diabetic neuropathy [ 25 ].…”