Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke

Abstract

Treatment options for stroke remain limited. Neuroprotective therapies, in particular, have invariably failed to yield the expected benefit in stroke patients, despite robust theoretical and mechanistic background and promising animal data. Insulin and insulin-like growth factor 1 (IGF-1) play a pivotal role in critical brain functions, such as energy homeostasis, neuronal growth, and differentiation. They may exhibit neuroprotective properties in acute ischemic stroke based upon their vasodilatory, anti-inflammatory and antithrombotic effects, as well as improvements of functional connectivity, neuronal metabolism, neurotransmitter regulation, and remyelination. Intranasally administered insulin has demonstrated a benefit for prevention of cognitive decline in older people, and IGF-1 has shown potential benefit to improve functional outcomes in animal models of acute ischemic stroke. The intranasal route presents a feasible, tolerable, safe, and particularly effective administration route, bypassing the blood-brain barrier and maximizing distribution to the central nervous system (CNS), without the disadvantages of systemic side effects and first-pass metabolism. This review summarizes the neuroprotective potential of intranasally administered insulin and IGF-1 in stroke patients. We present the theoretical background and pathophysiologic mechanisms, animal and human studies of intranasal insulin and IGF-1, and the safety and feasibility of intranasal route for medication administration to the CNS.

Fig. 1

Mechanisms implicated in the ischemic cascade and potential targets for insulin in response to acute ischemia. “Stop” signs indicate the steps of the ischemic cascade where insulin can intervene to limit the extent of ischemic damage. Notice that its impact can be exerted along several different steps and mechanisms, indicative of its pleiotropic effect

Fig. 2

The intranasal route of molecule transport to the CNS. Paracellular and axonal transport along the olfactory and trigeminal neurons results in increased concentrations in the highlighted brain areas (although not limited to those)