Neuroprotection by glucagon: role of gluconeogenesis

Abstract

Object The severity of neurological impairment following traumatic brain injury (TBI) is exacerbated by several endogenous processes, including hyperglycemia, hypotension, and the generation of glutamate. However, in addition to controlling hyperglycemia, insulin has pleiotropic effects on tissue metabolism, which include reducing the concentration of the neurotoxic amino acid glutamate, making it unclear whether insulin's beneficial effects are attributable to the establishment of euglycemia per se. In the present study, the authors asked if reducing glutamate via approaches that do not lower glucose levels would improve neurological outcome following TBI. Methods Glucagon activates gluconeogenesis by increasing the hepatic uptake of amino acids such as glutamate and facilitating their conversion to glucose. Glucagon was administered as a single intraperitoneal injection before or after closed head injury (CHI). Neurological function, brain histological features, blood glutamate and glucose levels, and CSF glutamate concentrations were measured. Results A single intraperitoneal injection of glucagon (25 μg) into mice 10 minutes before or after CHI reduced lesion size by about 60% (p < 0.0001) and accelerated neurological recovery. The neuroprotective effect of glucagon was related to gluconeogenesis by decreasing the concentration of the neuroexcitatory amino acid glutamate in the circulation from 207 ± 32.1 μmol/L in untreated mice to 101.11 ± 21.6 μmol/L in treated mice (p < 0.001); a similar effect occurred in the CSF. The neuroprotective effect of glucagon was seen notwithstanding the attendant increase in blood glucose, the final substrate of gluconeogenesis. Conclusions Glucagon exerts a marked neuroprotective effect post-TBI by decreasing CNS glutamate. Glucagon was beneficial despite increasing blood glucose. Favorable effects also occurred when glucagon was given prior to TBI, suggesting its involvement in the preconditioning process. Thus, glucagon may be of value in providing neuroprotection when administered after TBI or prior to certain neurosurgical or cardiac interventions in which the incidence of perioperative ischemia is high.