Abstract:

Acute ischemic stroke (AIS) is a leading cause of death and long-term disability in the USA and worldwide. Significant advances in the last two decades have resulted in introduction of intravenous tissue plasminogen activator and more recently catheter based endovascular interventions in selected patients. These interventions are applicable to a limited number of patients fulfilling specific criteria; therefore neuroprotection has attracted significant attention. Neuroprotection refers to strategies and interventions aiming to limit the extent of AIS-related injury and facilitate the naturally occurring regenerative mechanisms. Acute ischemic injury triggers a series of events in a cellular and molecular level, resulting in energy failure and ultimately neuronal death: Inflammation, excitotoxicity, apoptosis, reactive oxygen and nitrogen species formation, mitochondrial failure have been implicated in the ischemic cascade. In contrast to many other neuroprotective agents used in past clinical trials targeting specific single steps along the process, insulin’s effects are pleiotropic: It suppresses pro-inflammatory transcription factors and might limit the detrimental effect of the inflammatory response. It produces an antithrombotic effect by decreasing the tissue factor and plasminogen activator inhibitor-1 levels and a vasodilatory effect by promoting activation of endothelial nitric oxide synthase; both actions could facilitate recruitment of collateral vessels and enhance the effect of thrombolysis, ultimately reducing the final infarct volume and improving long-term functional outcome. Insulin also favorably regulates cerebral energy homeostasis. In addition to the acute phase, insulin’s effects extend to the subacute and chronic phase, exerting a potent antiapoptotic effect and promoting myelin and neurite regeneration, neurotransmission and functional connectivity of the brain. The intranasal route presents significant advantages: The absorption occurs mostly through paracellular transport and endocytosis, following the course of olfactory and trigeminal neurons that are present in the nasal cavity. This offers the significant advantage of bypassing the blood-brain barrier and achieving rapid, widespread CNS penetration (detected in the CNS within 1 hour from administration). Intranasally administered insulin possesses many of the ideal properties for acute stroke neuroprotection, due to it plurifunctional mechanism of action, wide applicability, safety and simplicity of CNS distribution. Well-designed animal and phase I human studies are necessary to improve our understanding of its neuroprotective potential in acute stroke.