Deuterium-containing sigma-1 agonist demonstrates anti-seizure, anti-inflammatory effects in TBI model
Published on March 24, 2015 at 1:53 AM ·
Research results published in the Journal of Neurotrauma and conducted by the Walter Reed Army Institute of Research (WRAIR) as part of a collaboration with Concert Pharmaceuticals, Inc. showed that a novel deuterium-containing sigma-1 agonist invented at Concert, called C-10068, demonstrated anti-seizure and anti-inflammatory effects in a preclinical model of traumatic brain injury (TBI). C-10068, a novel metabolically-stabilized morphinan derivative, is based on a compound first identified at WRAIR in the 1990s as possessing anticonvulsant properties. In the current study C-10068 demonstrated a statistically significant reduction in frequency and duration of seizures following TBI in a preclinical model developed at the WRAIR. C-10068 affects multiple neurochemical pathways, including sigma-1 receptors which have a widespread modulatory role in the central nervous system (CNS).1 The C-10068 study was conducted under a Cooperative Research and Development Agreement (CRADA) granted to Concert in collaboration with the WRAIR.
"We are highly encouraged by the results with C-10068 in this study. The compound previously demonstrated anti-seizure activity in multiple non-TBI animal models, and our preclinical testing with C-10068 similarly showed significant seizure protection in our unique model of refractory, TBI-induced brain seizure activity," said Dr. Frank Tortella, whose team conducted the studies for this CRADA in his lab at WRAIR, and who serves as Chief of the Brain Trauma Neuroprotection and Neuroplasticity Branch in the Center for Military Psychiatry and Neuroscience at the WRAIR.
"C-10068 represents an opportunity in our R&D pipeline that may be considered for advancement into the clinic in the future based on additional preclinical studies," said Nancy Stuart, Chief Operating Officer of Concert Pharmaceuticals. "C-10068 is another example of how applying deuterium chemistry can enhance the pharmacologic properties of novel therapeutics for CNS diseases, and builds on our pipeline of drug candidates for a range of CNS diseases including spasticity, narcolepsy, Alzheimer's agitation and major depressive disorder."
The purpose of the study published in the Journal of Neurotrauma was to evaluate the anti-seizure dose-response of C?10068 in a novel rat model of nonconvulsive seizures (NCS) induced by penetrating ballistic-like brain injury (PBBI). C-10068 was administered by continuous intravenous infusion in a saline vehicle, and the control group received vehicle alone. The results showed:
Reduction in NCS incidence: While 75% of vehicle-treated PBBI animals experienced NCS which occurred spontaneously during the 72 hour recording period, those treated with C-10068 had a 40-50% reduced NCS incidence independent of dose.
Reduction in NCS frequency and duration: On average, vehicle-treated animals had 8.3 NCS events per animal with total seizure duration of 379 seconds per animal. C-10068 treatments dose-dependently (low-to-high dose) reduced NCS frequency by 20%, 42%, and 70% (p<0.05) and NCS duration by 30%, 41%, and 82% (p<0.05).
Delay in onset of NCS: C-10068 treatment delayed the onset of NCS from 22 hour in the vehicle group to 43-46 hours across the C-10068 treated groups (p<0.05).
The highest dose of C-10068 also significantly attenuated neuroinflammatory responses (hippocampal astrocyte activation and peri-lesional microglial reactivity) following PBBI. The reduction in hippocampal astrocyte activation was positively correlated with reduction in NCS frequency.
The results demonstrated that post-injury administration of C-10068 provided significant protection against acute spontaneously occurring NCS observed following penetrating TBI, as well as attenuating the associated neuroinflammatory response. C-10068 binds to several potentially important CNS targets, including the sigma-1 receptor, with an overall pharmacological profile similar to dextroethorphan and dextromethorphan, both of which have established anti-seizure activities2,3.
Under the CRADA, entered in 2011, WRAIR conducted preclinical testing on C-10068, a novel compound derived from Concert's DCE Platform® (deuterated chemical entity platform) for seizure protection associated with traumatic brain injury (TBI). The CRADA further advanced Concert's research program for drug compounds that have demonstrated anti-seizure activity in preclinical models and may be effective in the treatment of various epileptic or seizure-generating diseases and injuries, such as ischemic stroke and traumatic brain injury.
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