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.

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

“…As previously reported (Lioutas et al, 2015), animals were anesthetized with isoflurane, 2μl per drop was given every 2min in alternating nares. siRNA sestrin2 (300 pmol/1μl, mixed by three different rat-derived siRNA with siRNA ID: SASI_Rn02_00247651, SASI_Rn02_00247652, SASI_Rn02_00247645, Sigma-Aldrich, USA), and scramble RNA (300 pmol/1μl) were delivered by intracerebroventricular injection, 2μl drug per pup injected slowly in 5min (Chen et al, 2015), at 1.5 mm posterior, 1.5mm lateral to the bregma and 1.7mm deep on the ipsilateral hemisphere at 24h pre HI.…”

Progress of Research on Diffuse Axonal Injury after Traumatic Brain Injury

“…Phosphorylated neurofilament was hydrolyzed and finally resulted in neurofilament collapse. Because NF-H can be detected in serum after onset of DAI and increased from 6 h, peaked at 12 h and 48 h, and decreased to normal level on day 7 [42, 43]. NF-H is considered the most convenient marker of DAI diagnosis.…”

Sex differences in stroke therapies

“…Studies using male animal models support the hypothesis that IGF-1 plays a pivotal role in maintaining brain functions in acute ischemic stroke through various mechanisms including neuronal survival, anti-inflammation, and/or anti-thrombotic effects (Jin et al 2013; Li et al 2010; Patel et al 2013). Exogenous IGF-1 treatment intranasally, intravenously, or intracerebroventricularly has been shown to decrease ischemic stroke injury (Lioutas et al 2015; Liu et al 2004; Rizk et al 2007; Sohrabji 2015). Female animal models have demonstrated that post-stroke IGF-1 replacement reverses estrogen’s neurotoxic effects in middle-aged ovariecotmized female rats (Selvamani and Sohrabji 2010a; Selvamani and Sohrabji 2010b).…”