Drug-induced hyperglycemia as a potential contributor to translational failure of uncompetitive NMDA receptor antagonists

Abstract

Hyperglycemia is a comorbidity in 60-80% of stroke patients; nevertheless, neuroprotective drugs like N-methyl-D-aspartate receptor (NMDAR) antagonists are typically assessed in normoglycemic animals at the preclinical stage before they are approved to enter clinical trials. Interestingly, as a possible explanation for the translational failure of NMDAR antagonists, it was recently reported that stroke occurring during nighttime causes smaller infarctions in rodents and therefore has a smaller window for neuroprotection. To investigate why stroke occurring during different circadian phases confers a difference in severity, we reanalyzed the published source data and found that some mice that were used in the daytime have higher blood glucose than mice that were used in the nighttime. We then repeated the experiments but found no difference in blood glucose concentration or infarct volume regardless of the circadian phase during which stroke occurs. On the other hand, induction of hyperglycemia by glucose injection reproducibly increased stroke severity. Moreover, although hyperglycemia increases infarction volume, which presumably would provide a larger window for neuroprotection, uncompetitive NMDAR antagonists were unexpectedly found to exacerbate stroke outcome by worsening hyperglycemia. Taken together, our new data and reanalysis of the published source data suggested that blood glucose during stroke, rather than the circadian phase during which stroke occurs, affects the size of the ischemic infarction; moreover, we have revealed drug-induced hyperglycemia as a potential reason for the translational failure of uncompetitive NMDAR antagonists. Future trials for this class of neuroprotective drugs should monitor patients’ blood glucose at enrollment and exclude hyperglycemic patients.

Significance Statement

Hyperglycemia is highly prevalent among stroke patients (60-80%) (Scott et al., 1999), and blood glucose is a chief determinant of stroke severity in the clinic. Nevertheless, preclinical stroke studies were typically performed using normoglycemic animals. Here, we reported evidence that uncompetitive NMDA receptor antagonists, a major class of neuroprotective drugs, can exacerbate stroke outcome in hyperglycemic and diabetic mice. Our study revealed a previously unknown explanation for the translational failure of NMDA receptor antagonists, thereby providing new guidance for the future design of clinical stroke trials. In addition, this report serves as a case for the need to assess neuroprotective drugs in hyperglycemic animals before they should be approved to treat stroke patients in clinical trials.