Impact of galanin receptors 2 and 3 double-knockout on neuroinflammation and functional recovery following traumatic brain injury

Abstract

Traumatic brain injury (TBI) is one of the world’s leading causes of death and disability in young individuals and the mechanism underlying TBI-associated neuroinflammation is poorly understood. The regulatory neuropeptide galanin (GAL) and its three receptors (GAL_1–3R) are assumed to modulate the neuroinflammatory response following TBI, especially by signalling via GAL₂R and GAL₃R. Therefore, the role of GALRs in acute neuroinflammation and functional recovery following moderate Controlled Cortical Impact TBI was studied using GAL_2/3R-double-KO (GAL_2/3R-KO) mice. Brains and cerebrospinal fluid (CSF) were collected at day 1 and 30 days post TBI. Functional recovery post TBI was assessed by the modified Neurological Severity Score (mNSS), Elevated Plus Maze (EPM) and Morris Water Maze (MWM) test. Post TBI (day 1–28 post injury), neurological dysfunction was more severe in GAL_2/3R-KO mice than in WT mice. At 1 day post TBI, inflammatory markers and several nerve growth factors significantly increased in the ipsilateral hemisphere, compared to the contralateral hemisphere in both GAL_2/3R-KO and WT mice. At 4 days post surgery, TBI mice entered significantly more frequent the open-arms in the EPM compared to Sham-operated mice, suggestive of increased exploratory behaviour in TBI mice. At 30 days post TBI, immunostaining of brain sections revealed significant differences in vascularisation and glial scarring in the cortex when comparing TBI and Sham-operated mice, but genotypes were similar. In summary, the results indicate that GAL₂R and/or GAL₃R have a neuroprotective role following moderate TBI, as the severity was significantly lower in their presence than in their absence.