Ivermectin's neuroprotective effects decrease with prolonged use after cerebral ischemia/reperfusion

Ivermectin (IVM), the recipient of the 2015 Nobel Prize, is an FDA-approved drug for a variety of parasitic diseases in animals and humans. However, the implications of this compound on neurological disorders remain inadequately elucidated. Recently, our research team has elucidated the neuroprotective properties of ivermectin administered in three doses following cerebral ischemia/reperfusion (IR). The objective of the current investigation is to ascertain whether ivermectin sustains its neuroprotective properties through prolonged administration in models of cerebral IR in rats, as well as to evaluate its impact on the formation of neutrophil extracellular traps (NETs). A rat model of transient global cerebral IR was induced by occluding both carotid arteries for 20 min. Ivermectin (2 mg/kg/day) was administered intraperitoneally one hour after the induction of cerebral ischemia for 7 consecutive days at 24-hour intervals. Then, the effects of ivermectin on brain infarct size, blood cell profile, bleeding time, memory and learning, balance and motor coordination, myeloperoxidase enzyme activity, and H3cit protein levels were investigated. The finding showed that the administration of ivermectin for 7 days did not improve memory and learning, blood parameters, or cerebral infarct size. However, it caused a 25.4% reduction in citrullinated histone protein level, decreased myeloperoxidase activity (P = 0.017), and improved balance and motor coordination (P = 0.017 and P = 0.024). In conclusion, our findings indicate that prolonged administration of ivermectin may diminish its neuroprotective effects and its effects can differ depending on the drug regimen.