Differential consequences of traumatic brain injury in male rat hippocampus hemispheres and the beneficial effect of neuropeptide Y.

Traumatic brain injury (TBI) initiates a complex cascade of secondary injury mechanisms, including neurovascular dysfunction, neuroinflammation, and glial activation, which progressively contribute to long-term neurological deficits. Although the primary mechanical insult is typically unilateral, secondary pathological processes can extend beyond the impact site. However, the spatiotemporal evolution of these bilateral alterations remains poorly understood. Neuropeptide Y (NPY) is an endogenous neuromodulator with anti-inflammatory and neuroprotective properties, making it a promising candidate for limiting secondary brain injury. Here, we characterized the bilateral hippocampal response to experimental TBI and evaluated whether early intranasal NPY administration post-TBI attenuates neurovascular and neuroinflammatory alterations while improving behavioral outcomes. Male Sprague-Dawley rats were subjected to a closed-head weight-drop model of TBI and treated intranasally with NPY (100 μg/animal) or vehicle 30 min after injury. Molecular, histological, and behavioral analyses were performed 48 h and 7 days post-injury. We concluded that TBI induced distinct spatiotemporal pathological responses in the hippocampi. The ipsilateral hippocampus exhibited early blood-brain barrier (BBB) disruption and astrocytic alterations, whereas the contralateral hippocampus developed a more pronounced and sustained inflammatory response characterized by microglial activation and increased expression of inflammatory and endothelial activation markers. Early intranasal NPY administration attenuated these bilateral pathological alterations by preserving BBB integrity, reducing neuroinflammatory responses, and normalizing glial morphology. These neurobiological effects were accompanied by improvements in spatial working memory and anxiety-related behaviors. Collectively, our findings demonstrate that unilateral TBI induces distinct bilateral secondary injury responses within the hippocampus and identify early intranasal NPY administration as a promising strategy. Further investigation is warranted to clarify the underlying mechanisms and establish the long-term therapeutic potential of NPY.