Hypoglycaemia is a common complication in insulin-dependent diabetes, and it can lead to brain damage and long-term cognitive impairment. A study published in the Journal of Neuroscience points towards a potential therapeutic target for treating patients with severe hypoglycaemia.

Hypoglycaemia seems to cause neuronal damage by initiating a cascade of events that includes a large increase in extracellular glutamate in the brain. Sustained activation of glutamate receptors leads to excitotoxicity, DNA damage and cell death, and also causes activation of poly(ADP-ribose) polymerase 1 (PARP1), which is involved in DNA repair. Extensive activation of PARP1 can lead to cell death, and this is thought to be an important mediator of glutamate toxicity.

Suh et al. found that cortical cultures derived from PARP1-knockout mice, or cultures treated with a PARP1 inhibitor, were largely resistant to hypoglycaemic neuronal death. And in a rat model of hypoglycaemia produced by injection of insulin, a PARP1 inhibitor reduced neuronal damage in the cortex and hippocampus by up to 80% — even if given as late as two hours after the hypoglycaemic episode.

As well as protecting the vulnerable neurons against hypoglycaemic damage, the PARP1 inhibitor also prevented the cognitive dysfunction (in particular, deficits in spatial learning and memory) that was seen in untreated animals after hypoglycaemia.

At present, the only treatment for hypoglycaemia in humans is to raise blood glucose by giving glucose or the hormone glucagon, but this does not prevent ongoing brain damage. If PARP1 inhibitors could be shown to work in humans, even when given after normalization of blood glucose levels, they would be a valuable addition to the medical toolbox.