Glucagon-like peptide-1 (GLP-1)-based therapies, GLP-1 receptor agonists (GLP-1RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is) are widely used for the treatment of type 2 diabetes. Increasing evidence suggests that they may provide neuroprotection. The aim of this MiniReview was to systematically evaluate the proposed mechanism of action for GLP-1-based therapies in ischaemic brain damage in animals. We performed a literature search using MEDLINE, EMBASE and The Cochrane Library. GLP-1-based therapies administered before, during or after experimental stroke in diabetic and non-diabetic animals were evaluated. We reviewed 27 studies comprised of 20 involving GLP-1RAs and seven involving DPP-4Is. Both GLP-1RAs and DPP-4Is affected the acute inflammatory response secondary to ischaemia by reducing inflammation, endothelial leakage and excitotoxicity. Both treatments also reduced oxidative stress and apoptosis. GLP-1RAs significantly reduced infarct volume when administered acutely, but not later after stroke. The reported effects of DPP-4Is on infarct volume were inconsistent. GLP-1-RAs reliably improved functional outcome, but the effects on cerebral blood flow were inconclusive. These neuroprotective effects were often attributed to activation of the GLP-1 receptor, but non-GLP-1R-mediated effects have also been suggested. Both GLP-1RAs and DPP-4Is significantly affected inflammation, oxidative stress and apoptosis in animal stroke models; however, data from clinical trials only report therapeutic efficacy for GLP-1RAs. Thus, GLP-1RA administration is the most promising treatment to pursue for patients at risk of stroke or immediately after stroke. Future studies should address acute and prophylactic treatments in stroke patients with and without diabetes.

Phosphodiesterase 5 inhibitors (PDE5i), such as sildenafil (Viagra®) are widely used for erectile dysfunction and pulmonary hypertension. Preclinical studies suggest that PDE5i may improve functional outcome following ischemic stroke. In this systematic review we aimed to evaluate the effects of selective PDE5i in animal models of brain ischaemia. A systematic search in Medline, Embase, and The Cochrane Library was performed including studies in English assessing the effects of selective PDE5i. 32 publications were included describing outcome in 3646 animals. Neuroprotective effects of PDE5i were dependent on the NO-cGMP-PKG-pathway. These included reduced neuronal apoptosis (n=3 studies), oxidative stress (n=5), and neuroinflammation (n=2). PDE5i increased angiogenesis and elevated regional cerebral blood flow in the ischemic penumbra, and improved functional recovery. Some studies found that PDE5i treatment reduced lesion volume (n=9), others found no effect (n=9). Treatment was effective when administered within 24h post-ischemia, though treatment delayed to seven days improved outcome in one study. This review demonstrates both neuroprotective and neurorestorative effects of PDE5i in animal models of stroke, though the specific underlying signaling pathways relating to PDE5 inhibition and cGMP may remain serendipitous in some studies. There is currently limited evidence on the effects of selective PDE5i in human stroke patients, hence translation of preclinical results into clinical trials may be warranted.

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