Preclinical and clinical studies have shown therapeutic potential of mild-to-moderate
hypothermia for treatments of
stroke and
traumatic brain injury (TBI). Physical cooling in humans, however, is usually slow, cumbersome, and necessitates sedation that prevents early application in clinical settings and causes several side effects. Our recent study showed that pharmacologically
induced hypothermia (PIH) using a novel
neurotensin receptor 1 (NTR1) agonist,
HPI-201 (also known as ABS-201), is efficient and effective in inducing
therapeutic hypothermia and protecting the brain from ischemic and
hemorrhagic stroke in mice. The present investigation tested another second-generation NTR1 agonist,
HPI-363, for its hypothermic and protective effect against TBI. Adult male mice were subjected to controlled cortical impact (CCI) (velocity=3 m/sec, depth=1.0 mm, contact time=150 msec) to the exposed cortex. Intraperitoneal administration of
HPI-363 (0.3 mg/kg) reduced body temperature by 3-5°C within 30-60 min without triggering a shivering defensive reaction. An additional two
injections sustained the hypothermic effect in conscious mice for up to 6 h. This PIH treatment was initiated 15, 60, or 120 min after the onset of TBI, and significantly reduced the
contusion volume measured 3 days after TBI.
HPI-363 attenuated
caspase-3 activation, Bax expression, and TUNEL-positive cells in the pericontusion region. In blood-brain barrier assessments,
HPI-363 ameliorated extravasation of
Evans blue dye and
immunoglobulin G, attenuated the MMP-9 expression, and decreased the number of microglia cells in the post-TBI brain.
HPI-363 decreased the
mRNA expression of
tumor necrosis factor-α and interleukin-1β (IL-1β), but increased
IL-6 and
IL-10 levels. Compared with TBI control mice,
HPI-363 treatments improved sensorimotor functional recovery after TBI. These findings suggest that the second generation NTR-1 agonists, such as
HPI-363, are efficient hypothermic-inducing compounds that have a strong potential in the management of TBI.