Persistent activation of the N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) – including the extra-synaptic ones – is known to underlie the pathogenesis of a number of neurological disorders, including Alzheimer's disease, amyotrophic lateral sclerosis or stroke. This phenomenon, known as excitotoxicity, causes neuronal apoptotic death. Glycolysis is widely considered a pro-survival metabolic pathway because it meets the energy needs of cells during mitochondrial bioenergetic stress. However, the metabolic use of glucose through glycolysis in neurons is normally very low, being mainly metabolized through the pentose-phosphate pathway (PPP), a metabolic route that contributes to the maintenance of neuronal redox status.
A key factor that determines these metabolic features is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase- 3 (PFKFB3), a pro-glycolytic enzyme that is normally absent in neurons but abundant in astrocytes. Notably, under certain neuropathological conditions, such as during excitotoxicity, the PFKFB3 protein levels stabilize, active neuronal PFKFB3 then stimulates glucose consumption through glycolysis, which results in a concomitant decreased PPP to cause redox stress and, eventually, apoptotic death.
We demonstrated that pharmacological inhibition of PFKFB3
- protected neurons from apoptotic death upon excitotoxic insults in vitro by preventing the redox stress associated with glycolytic activation
- was neuroprotective against Aß25-35 in vitro treatment and prevents protein aggregate formation in SY5Y/APPsw in vitro model
- protected against motor discoordination and brain damage in a mouse model of brain ischemia/reperfusion the middle carotid artery occlusion (MCAO) ischemia/reperfusion model
These results show that pharmacological inhibition of PFKFB3 is a suitable neuroprotective therapeutic strategy for excitotoxicity-related neurological diseases.