GP Inhibitor DAB Ameliorates Acute Epileptic Seizures,memory Deficits And Neuroinflammation In PTZ Epilepsy Rats

[Background and Objective]Epilepsy is a complex neurological syndrome characterized by excessive excitation and sudden synchronized dischargesof neurons.Brain neurons repeatedly discharge abnormally,resulting in neuron loss and apoptosis,which leads to different degrees of learning and memory and cognitive dysfunction.The current anti-epileptic drugs(AEDs)are to control the occurrence of epileptics,rather than delay the pathological process of epilepsy,and often cause side effects.Therefore,finding new antiepileptic drug targets remains a huge challenge.Studies have shown that fructose-1,6-bisphosphate,lactate dehydrogenase inhibitors,and hexokinase inhibitors have antiepileptic effects on the acute epilepsy model in rats.Their common mechanism is to inhibit glycolysis and reduce lactate production,suggests that lactate plays a very important role in acute seizures.Glycogen phosphorylase(GP)is a key enzyme that regulates glycogen-derived lactate production in astrocytes.It is responsible for catalytic decomposition of glycogen into glucose-6-phosphate,thereby promoting lactate production.This study explored the improvement effect of GP inhibitor DAB on pentylenetetrazole(PTZ)-induced epileptic seizures,memory deficits and neuroinflammation in rats and the reversing effect of exogenous lactate on DAB.[Methods] 1.A single intraperitoneal injection(i.p.)of PTZ(70mg/kg)induced acute epilepsy in rats.2.Racine scoring criteria for offline assessment of acute epilepsy-like behavior in rats.3.Spontaneous activity test,novel object recognition test(NOR)to evaluate memory function in rats.4.Colorimetric detection of lactate levels in the hippocampus of rats.5.Western blot was used to detect the expression of GP in hippocampus and the expression of inflammatory response indicators(IL-1?,IL-6,TNF-?,IBA-1,GFAP)in rats.[Results]PTZ up-regulated the levels of lactate and GP in the hippocampus of rats.DAB prolonged seizure latency,reduced seizure duration,and reduced seizure scores in epileptic rats.DAB increases discrimination index of novel object recognition test in epileptic rats.DAB down-regulated PTZ-induced hippocampal IL-1?,TNF-?,IBA-1,and GFAP expression.L-lactate reversed the ameliorative effect of DAB on acute epileptic seizures and cognitive impairment induced by PTZ.L-lactate reversed DAB down-regulation of PTZ-induced hippocampal IL-1?,IL-6,TNF-?,IBA-1,and GFAP expression.[Conclusion]Glycogen phosphorylase inhibitor DAB ameliorates PTZ-induced acute epileptic seizures,memory deficits and neuroinflammation in rats by down-regulating lactate.