Mechanisms of action of acute and subacute sphenopalatine ganglion stimulation for ischemic stroke

Background Sphenopalatine ganglion stimulation (SPG-Stim) for ischemic stroke, starting 8-24 h after onset and continuing through five days in a pooled analysis of two recent, randomized, sham-controlled trials, improved outcome of acute ischemic stroke patients with confirmed cortical involvement. As a neuromodulatory therapy, SPG-Stim differs substantially from existing pharmacologic (lytic and antiplatelets) and device (endovascular thrombectomy) acute ischemic stroke treatments. Aim Focused review of SPG anatomy, physiology, and neurovascular and neurobiologic mechanisms of action mediating benefit of SPG-Stim in acute ischemic stroke. Summary of review Located posterior to the maxillary sinus, the SPG is the main source of parasympathetic innervation to the anterior circulation. Preclinical and human studies delineate four distinct mechanisms of action by which the SPG-Stim may confer benefit in acute ischemic stroke: (1) collateral vasodilation and enhanced cerebral blood flow, mediated by release of neurotransmitters with vasodilatory effects, nitric oxide, and acetylcholine, (2) stimulation frequency- and intensity-dependent stabilization of the blood-brain barrier, reducing edema (3) direct acute neuroprotection from activation of the central cholinergic system with resulting anti-inflammatory, anti-apoptotic, and anti-excitatory effects; and (4) neuroplasticity enhancement from enhanced central cholinergic and adrenergic neuromodulation of cortical networks and nitrous oxide release stimulating neurogenesis. Conclusion The benefit of SPG-Stim in acute ischemic stroke is likely conferred not only by potent collateral augmentation, but also blood-barrier stabilization, direct neuroprotection, and neuroplasticity enhancement. Further studies clarifying the relative contribution of these mechanisms and the stimulation protocols that maximize each may help optimize SPG-Stim as a therapy for acute ischemic stroke.