Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Abstract

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 six-hour 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 15 min or 2 hr 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.

Neural Stem Cells Expressing bFGF Reduce Brain Damage and Restore Sensorimotor Function after Neonatal Hypoxia-Ischemia

“…Neonatal hypoxia-ischemia (HI) leads to severe brain damage and increases neonatal morbidity and mortality，which becomes a major global health problem [1-4]. The effect of current treatment for neonatal (HI) is limited.…”

Magnesium Lithospermate B Implicates 3′-5′-Cyclic Adenosine Monophosphate/Protein Kinase A Pathway and N -Methyl- d -Aspartate Receptors in an Experimental Traumatic Brain Injury

“…Another way to evaluate brain edema is by using magnetic resonance imaging. A number of pharmacologic substances and medical techniques, including glutamate receptor antagonists (19,27), calcium channel antagonists (20), free radical scavengers (9,34), and 32 C hypothermia (18), have been investigated for their ability to ameliorate TBI-induced secondary damage. Although until the present no drug has achieved this goal, the treatment with MLB exerts a neuroprotective effect in the TBI rats by a cAMPdependent mechanism and merits further study.…”

“…MLB is proven to be able to improve the endothelial function of vessel walls by inducing sGC-a in animals subject to TBI. Guanine nucleotidyl cyclase is a signal-transduction enzyme that serves as a receptor for atrial, natriuretic peptides, NO, and carbon monoxide (CO) (18). In the study by Mergia et al (29), nanomolar concentrations of NO, catalyzed by endothelial NO synthase, can act on the NO-sensitive sGCa1b1 and sGCa2b1.…”

Pharmacological hypothermia: a potential for future stroke therapy?

“…95 Recently, neurotensin analog HPI201 (formerly ABS201) has been studied in ischemic stroke and ICH models, and HPI363 analog has been studied in a traumatic brain injury (TBI) model. HPI201 administered at 2 mg/kg followed by another 1 mg/kg dose caused a 2-5 °C reduction in body temperature that persisted for 6 h in ischemic stroke model in rats 96 and mice. 97 Administration of HPI201 has also been shown to lead to mild hypothermia at 32.7 ± 0.4 °C in an ICH model in mice.…”