l‐Lactate mediates neuroprotection against ischaemia by increasingTREK1 channel expression in rat hippocampal astrocytesin vitro

Abstract Brain ischaemia is a highly debilitating condition where shortage of oxygen and glucose leads to profuse cell death. Lactate is a neuroprotective metabolite whose concentrations increase up to 15–30 mmol/L during ischaemia and TREK 1 is a neuroprotective potassium channel which is upregulated during ischaemia. The aim of this study was to investigate the effect of l ‐lactate on TREK 1 expression and to evaluate the role of l ‐lactate‐ TREK 1 interaction in conferring neuroprotection in ischaemia‐prone hippocampus. We show that 15–30 mmol/L l ‐lactate increases functional TREK 1 protein expression by 1.5–3‐fold in hippocampal astrocytes using immunostaining and electrophysiology. Studies with transcription blocker actinomycin‐D and quantitative PCR indicate that the increase in TREK 1 expression is due to enhanced TREK 1 mRNA transcription. We further report that l ‐lactate‐mediated increase in TREK 1 expression is via protein kinase A ( PKA )‐dependent pathway. This is the first report of an ischaemic metabolite affecting functional expression of an ion channel. Our studies in an in vitro model of ischaemia using oxygen glucose deprivation show that 30 mmol/L l ‐lactate fails to reduce cell death in rat hippocampal slices treated with TREK 1 blockers, PKA inhibitors and gliotoxin. The above effects were specific to l ‐lactate as pyruvate failed to increase TREK 1 expression and reduce cell death. l ‐Lactate‐induced TREK 1 upregulation is a novel finding of physiological significance as TREK 1 channels contribute to neuroprotection by enhancing potassium buffering and glutamate clearance capacity of astrocytes. We propose that l ‐lactate promotes neuronal survival in hippocampus by increasing TREK 1 channel expression via PKA pathway in astrocytes during ischaemia. image Insufficient blood supply to the brain leads to cerebral ischaemia and increase in extracellular lactate concentrations. We incubated hippocampal astrocytes in lactate and observed increase in TREK1 channel expression via protein kinase A (PKA). Inhibition of TREK1, PKA and metabolic impairment of astrocytes prevented lactate from reducing cell death in ischaemic hippocampus. This pathway serves as an alternate mechanism of neuroprotection. Cover image for this issue: doi: 10.1111/jnc.13326 .