Neonatal
brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate
hypothermia has shown promising potential against
brain injuries induced by
stroke and
traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated
hypothermia. In addition,
general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically
induced hypothermia (PIH) using the
neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in
stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the
contusion volume versus TBI controls. Attenuation occurs whether
hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the
contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the
Evans Blue assay. HPI201 significantly decreased MMP-9 levels and
caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-
contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory
tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and
IL-6. In sensorimotor activity assessments, rats in the HPI201 treated group exhibited improved functional recovery after TBI versus controls. These data support that PIH
therapy using our NTR agonist is effective in reducing neuronal and BBB damage, attenuating inflammatory response and detrimental cellular signaling, and promoting functional recovery after TBI in the developing brain, supporting its potential for further evaluation towards clinical development.