Neuroprotective effects of ivermectin against transient cerebral ischemia-reperfusion in rats.

Stroke is a leading cause of disability and death worldwide. Ivermectin is a broad-spectrum anti-parasitic agent with potential anti-bacterial, anti-viral, and anti-cancer effects. However, the effects of ivermectin on the brain are poorly described. This study examined the effects of ivermectin on cerebral ischemia-reperfusion (IR) in rats. A rat model of transient global IR was induced by bilateral carotid artery occlusion for 20 min. Rats received ivermectin (2 mg/kg/day, ip) one hour after inducing cerebral IR for three consecutive days at 24-h intervals. Next, we examined the effects of ivermectin on brain infarction, histopathology, malondialdehyde levels, myeloperoxidase activity, spatial learning and memory, and phospho-AMPK protein levels. The results showed that ivermectin reduced brain infarct size (P < 0.001) and histopathological changes such as cerebral leukocyte accumulation and edema (P < 0.05) compared to untreated rats with IR. Treatment with ivermectin also decreased myeloperoxidase activity (P < 0.01) and malondialdehyde levels (P < 0.05) while increasing AMPK activity (P < 0.001), memory, and learning compared to the untreated IR group. Overall, we show for the first time that ivermectin conferred neuroprotective effects in a rat model of cerebral IR. Our results indicate that three days of treatment with ivermectin reduced brain infarct size, lipid peroxidation, and myeloperoxidase activity and improved memory and learning in rats with cerebral IR. These effects likely occurred via AMPK-dependent mechanisms.

Prenatal stress and increased susceptibility to anxiety-like behaviors: role of neuroinflammation and balance between GABAergic and glutamatergic transmission.

Neuroplasticity during the prenatal period allows neurons to regenerate anatomically and functionally for re-programming the brain development. During this critical period of fetal programming, the fetus phenotype can change in accordance with environmental stimuli such as stress exposure. Prenatal stress (PS) can exert important effects on brain development and result in permanent alterations with long-lasting consequences on the physiology and behavior of the offspring later in life. Neuroinflammation, as well as GABAergic and glutamatergic dysfunctions, has been implicated as potential mediators of behavioral consequences of PS. Hyperexcitation, due to enhanced excitatory transmission or reduced inhibitory transmission, can promote anxiety. Alterations of the GABAergic and/or glutamatergic signaling during fetal development lead to a severe excitatory/inhibitory imbalance in neuronal circuits, a condition that may account for PS-precipitated anxiety-like behaviors. This review summarizes experimental evidence linking PS to an elevated risk to anxiety-like behaviors and interprets the role of the neuroinflammation and alterations of the brain GABAergic and glutamatergic transmission in this phenomenon. We hypothesize this is an imbalance in GABAergic and glutamatergic circuits (as a direct or indirect consequence of neuroinflammation), which at least partially contributes to PS-precipitated anxiety-like behaviors and primes the brain to be vulnerable to anxiety disorders. Therefore, pharmacological interventions with anti-inflammatory activities and with regulatory effects on the excitatory/inhibitory balance can be attributed to the novel therapeutic target for anxiety disorders.