Neuroprotective Properties of Lithium Chloride in a Model of Neonatal Ischemia-Hypoxia

Abstract

Introduction. Neonatal ischemia-hypoxia is a severe complication of the perinatal period, leading to high mortality and persistent neurological impairments in surviving children. Current treatment methods, such as therapeutic hypothermia, have limited efficacy, necessitating the search for new neuroprotective strategies. Lithium, known for its neuroprotective properties in other forms of ischemic CNS injury, is of interest for application in neonatal practice. The aim of this study was to evaluate the neuroprotective effects of lithium chloride in a model of neonatal ischemia-hypoxia in newborn rats using magnetic resonance imaging (MRI) and a comprehensive analysis of neurological status.

Methods. The study was performed on neonatal Wistar rat pups (P7, n=44). The ischemia-hypoxia model was reproduced using a modified Rice-Vannucci protocol: the left common carotid artery was ligated, after which the animals were subjected to hypoxia (8% O₂, 92% N₂) for 2 hours. Sixty minutes after ischemia, the pups received intraperitoneal injections of either 0.9% sodium chloride solution (control, n=10) or 4.2% lithium chloride solution at a dose of 63 mg/kg (experimental group, n=10) for three days. Neurological status assessment was performed on days 3, 8, 14, and 28 using a battery of tests: forelimb and hindlimb grasping reflexes, cliff avoidance reaction, acoustic startle response, eye opening, and the limb placement test. On day 7, brain MRI was performed on a 7 T scanner with calculation of the lesion volume based on T2-weighted images. Statistical analysis was performed using the Mann-Whitney U-test.

Results. MRI revealed a significant reduction in brain lesion volume in the experimental group — 7.3 mm³ versus 14.1 mm³ in the control group (p=0.0001), corresponding to a 48% decrease. Neurological testing showed improvement in the experimental group in several parameters: forelimb grasping reflex on day 3 (p=0.0451), cliff avoidance reaction on day 8 (p=0.0208), acoustic startle response on day 14 (p=0.045), and the limb placement test on day 28 (p=0.045). No statistically significant differences were found for the hindlimb grasping reflex and eye opening.

Conclusion. Lithium chloride demonstrated a pronounced neuroprotective effect in the model of neonatal ischemia-hypoxia, significantly reducing brain lesion volume and improving functional outcomes. The obtained data justify the potential for further study of lithium as an adjuvant therapy for hypoxic-ischemic encephalopathy in newborns.