Accumulating preclinical data suggest that DPP-4 inhibitors might exert neuroprotective actions in animal models of ischemic stroke. In diabetic mice, administration of linagliptin for 4 weeks prior to transient middle cerebral artery occlusion-induced stroke resulted in a noticeable, albeit not statistically significant, trend towards reduction of stroke volume [
40]. In contrast, glimepiride had no effect on stroke volume [
40]. Moreover, stereological counting of surviving neurons revealed significantly more (approximately 30%) surviving neurons in linagliptin-treated mice than in glimepiride-treated animals [
40]. Therefore, treatment with linagliptin prior to ischemic stroke appears to exert neuroprotective effects [
40]. These effects appear to be unrelated to the glucose-lowering effect of linagliptin. Indeed, glucose levels decreased to a similar degree in linagliptin- and glimepiride-treated mice [
40]. Moreover, in non-diabetic mice, both linagliptin and glimepiride induced a comparable and non-significant reduction in stroke volume and an increase in the number of surviving neurons [
40]. In another study in non-diabetic mice, treatment with alogliptin for 3 weeks prior to ischemic stroke also reduced the volume of the infracted lesion and alleviated the severity of neurological deficit [
41]. In contrast with GLP-1 receptor agonists, DPP-4 inhibitors do not appear to cross the blood–brain barrier [
42]. It is possible that the neuroprotective effects of DPP-4 inhibitors are due to an increase in GLP-1 levels in the brain [
40]. However, other investigators showed that the beneficial effects of DPP-4 inhibitors in animal models of ischemic stroke are independent of GLP-1 [
43,
44]. Another possible explanation is that DPP-4 has many other substrates except GLP-1, including peptides with potential neurotrophic or neuroprotective effects [
45,
46]. These include glucose-dependent insulinotropic polypeptide, pituitary adenylate cyclase-activating polypeptide, and stromal cell-derived factor 1a (SDF-1a) [
47‐
49]. In preclinical models, these peptides were shown to promote synaptic plasticity, neurogenesis and neuronal differentiation, to inhibit apoptosis, and to reduce stroke size [
47‐
49]. Indeed, linagliptin increased brain SDF-1a levels in mice subjected to stroke whereas inhibition of SDF-1a abolished the beneficial effects of linagliptin on stroke volume and motor function [
44]. In addition, alogliptin was shown to increase the levels of brain-derived neurotrophic factor (BDNF), a potent brain neuroprotective cytokine, both in the cortex and in the whole forebrain [
41]. Notably, acute administration of linagliptin at the time of stroke does not affect the outcome; therefore, it is questionable whether DPP-4 inhibitors have a role in the acute management of patients with ischemic stroke [
43]. Despite these promising results of preclinical studies, there are very few data regarding the role of DPP-4 inhibitors in improving the outcome of patients with acute ischemic stroke. In a small study (
n = 123), we reported that patients who were hospitalized with acute ischemic stroke and were treated with DPP-4 inhibitors prior to stroke had a trend for less severe stroke at admission and also had better functional outcome and lower in-hospital mortality than patients treated with other antihyperglycemic agents [
50].