Abstract
PurposeThe Sonic Hedgehog (Shh) pathway has been associated with a protective role after injury to the central nervous system (CNS). We, therefore, investigated the effects of intrathecal Shh-administration in the subacute phase after thoracic spinal cord injury (SCI) on secondary injury processes in rats.MethodsTwenty-one Wistar rats were subjected to thoracic clip-contusion/compression SCI at T9. Animals were randomized into three treatment groups (Shh, Vehicle, Sham). Seven days after SCI, osmotic pumps were implanted for seven-day continuous intrathecal administration of Shh. Basso, Beattie and Bresnahan (BBB) score, Gridwalk test and bodyweight were weekly assessed. Animals were sacrificed six weeks after SCI and immunohistological analyses were conducted. The results were compared between groups and statistical analysis was performed (p < 0.05 was considered significant).ResultsThe intrathecal administration of Shh led to significantly increased polarization of macrophages toward the anti-inflammatory M2-phenotype, significantly decreased T-lymphocytic invasion and significantly reduced resident microglia six weeks after the injury. Reactive astrogliosis was also significantly reduced while changes in size of the posttraumatic cyst as well as the overall macrophagic infiltration, although reduced, remained insignificant. Finally, with the administration of Shh, gain of bodyweight (216.6 ± 3.65 g vs. 230.4 ± 5.477 g; p = 0.0111) and BBB score (8.2 ± 0.2 vs. 5.9 ± 0.7 points; p = 0.0365) were significantly improved compared to untreated animals six weeks after SCI as well.ConclusionIntrathecal Shh-administration showed neuroprotective effects with attenuated neuroinflammation, reduced astrogliosis and improved functional recovery six weeks after severe contusion/compression SCI.
Highlights
Hao Zhang and Alexander Younsi contributed to this work.Despite decades of research, spinal cord injury (SCI) remains a disastrous event, often associated with patients’ lifelong disability and high socioeconomic costs [1, 2]
To evaluate the inflammatory response after SCI, we quantified the infiltration of macrophages on spinal cord cross sections stained for the macrophagic marker Iba1 (Fig. 1a + b)
We concluded that while increased macrophagic infiltration is present in the injured spinal cord six weeks after thoracic contusion/compression SCI, the i.t. administration of Sonic Hedgehog (Shh) is unable to modulate this aspect of neuroinflammation
Summary
Hao Zhang and Alexander Younsi contributed to this work.Despite decades of research, spinal cord injury (SCI) remains a disastrous event, often associated with patients’ lifelong disability and high socioeconomic costs [1, 2]. Experimental treatment strategies aiming to attenuate such secondary injury processes and to improve functional recovery after SCI have been the focus of many preclinical studies, but the results have been varying and translation into the clinical practice has been proven to be difficult [4, 7]. Ongoing mitogenic activity of Shh during adulthood in response to neural tissue injuries such as ischemia or trauma has been postulated [16, 17]. We, aimed to assess the neuroprotective capacity of intrathecally administered Shh for the attenuation of the neuroinflammatory response, astrogliosis and cyst formation after thoracic contusion/compression SCI in rats with possible implications for functional recovery
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