Lithium Attenuates Brain Injury and Inflammation in Neonatal Rats withGerminal Matrix Hemorrhage

Introduction/Objective: Germinal matrix hemorrhage (GMH) is a major cause of mortality and neurodevelopmental disability in very preterm infants (<32 gestation weeks). This study evaluated lithium’s neuroprotective effects in a neonatal rat model of GMH. Methods: GMH was induced in postnatal day (P) 5 Sprague-Dawley rats via collagenase injections. Lithium chloride (LiCl) was administered intraperitoneally at 2 mmol/kg 6 hours post-injury, followed by 1 mmol/kg/day until P11. Brain injury, white matter integrity, inflammation, and neurobehavioral outcomes were assessed using MRI, histology, behavioral tests, and molecular analyses for key markers. A total of 107 pups were included Results: Lithium treatment reduced ipsilateral lesion volume by 37% (p < 0.01), improved fractional anisotropy in the hippocampus at P40 (p < 0.001), and alleviated anxiety-like behavior (p = 0.0089). It enhanced neural stem cell proliferation, supported oligodendrocyte survival, and reduced activation of microglia (Iba-1+ /CD68+ ) and astrocytic (GFAP+ ) (all p < 0.001). Molecular analyses showed increased phosphorylation of GSK-3β levels (p = 0.0002), elevated BDNF (p = 0.0108) and Cyclin D1 expression (p = 0.0183), and reduced IL-1β (p = 0.0025), indicating lithium modulates neuroinflammatory and neurotrophic pathways. Discussion: These findings support the role of lithium in mitigating brain injury after GMH, likely through the modulation of neuroinflammation, promotion of neurogenesis, and modulation of key molecular pathways (GSK-3β, BDNF, Cyclin D1, IL-1β), highlighting its translational promise. Conclusion: Lithium mitigates brain injury and neuroinflammation after GMH in neonatal rats, likely via GSK-3β inhibition and BDNF-mediated signaling. These findings highlight lithium’s therapeutic potential for improving outcomes in preterm infants