Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats.
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.
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xiaohuan
X
Gu
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA 30033, USA.
Zheng Zachory
ZZ
Wei
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Alyssa
A
Espinera
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Jin Hwan
JH
Lee
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xiaoya
X
Ji
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Ling
L
Wei
Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA.|JT Pharmaceuticals Inc, Mt. Pleasant, SC, 29464.
Thomas A
TA
Dix
Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA 30322, USA.|Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, GA 30033, USA.
Shan Ping
SP
Yu
D000818:Animals; D000831:Animals, Newborn; D001814:Blood-Testis Barrier / Q000187:drug effects / Q000473:pathology; D001831:Body Temperature / Q000187:drug effects* / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007036:Hypothermia, Induced; D020287:In Situ Nick-End Labeling; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
C575024:ABS-201; D053583:Interleukin-1beta; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; D010751:Phosphopyruvate Hydratase
Brain protection; Cell death; Drug-induced hypothermia; Functional recovery; Neonates; Traumatic brain injury