Abstract
Neonatal hypoxia–ischemia (HI) is one of the main causes of tissue damage, cell death, and imbalance between neuronal excitation and inhibition and synaptic loss in newborns. GABA, the major inhibitory neurotransmitter of the central nervous system (CNS) in adults, is excitatory at the onset of neurodevelopment and its action depends on the chloride (Cl−) cotransporters NKCC1 (imports Cl−) and KCC2 (exports Cl−) expression. Under basal conditions, the NKCC1/KCC2 ratio decreases over neurodevelopment. Thus, changes in this ratio caused by HI may be related to neurological disorders. The present study evaluated the effects of bumetanide (NKCC cotransporters inhibitor) on HI impairments in two neurodevelopmental periods. Male Wistar rat pups, 3 (PND3) and 11 (PND11) days old, were submitted to the Rice-Vannucci model. Animals were divided into 3 groups: SHAM, HI-SAL, and HI-BUM, considering each age. Bumetanide was administered intraperitoneally at 1, 24, 48, and 72 h after HI. NKCC1, KCC2, PSD-95, and synaptophysin proteins were analyzed after the last injection by western blot. Negative geotaxis, righting reflex, open field, object recognition test, and Morris water maze task were performed to assess neurological reflexes, locomotion, and memory function. Tissue atrophy and cell death were evaluated by histology. Bumetanide prevented neurodevelopmental delay, hyperactivity, and declarative and spatial memory deficits. Furthermore, bumetanide reversed HI-induced brain tissue damage, reduced neuronal death and controlled GABAergic tone, maintained the NKCC1/KCC2 ratio, and synaptogenesis close to normality. Thereby, bumetanide appears to play an important therapeutic role in the CNS, protecting the animals against HI damage and improving functional performance.
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DNM and CAN contributed to the conception and design of the study; DNM, LEDC, FKO, AVSC, APRM, LMS, MMM, GPB, and CD contributed to the acquisition and analysis of data; DNM, CAN, and LEDC contributed to drafting the text.
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Machado, D.N., Durán-Carabali, L.E., Odorcyk, F.K. et al. Bumetanide Attenuates Cognitive Deficits and Brain Damage in Rats Subjected to Hypoxia–Ischemia at Two Time Points of the Early Postnatal Period. Neurotox Res 41, 526–545 (2023). https://doi.org/10.1007/s12640-023-00654-3
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DOI: https://doi.org/10.1007/s12640-023-00654-3