CM352 Reduces Brain Damage and Improves Functional Recovery in a Rat Model of Intracerebral Hemorrhage

Abstract

BackgroundIntracerebral hemorrhage (ICH) is an acute neurological disorder with high mortality and no effective treatment. In addition to the initial bleeding event, rebleeding and hematoma expansion are associated with poor outcome in these patients. We studied the effectiveness of the new antifibrinolytic agent CM352, a short‐half‐life matrix metalloproteinase inhibitor, for achieving early hemostasis and improving functional recovery in a rat model of collagenase‐induced ICH.Methods and Results ICH was induced by striatal injection of collagenase, and 1 hour later, rats received an intravenous injection of saline (n=6) or CM352 (1 mg/kg, n=6). Hematoma (basal and after 3 and 24 hours) and lesion (14 days) volumes were quantified on T2‐weighted (T2) magnetic resonance images. Neurological and functional recovery was evaluated by using Bederson score and a cylinder test (basal, 24 hours, and 14 days). Early treatment (1 hour) with CM352 was efficient reducing hematoma expansion at 3 hours (P<0.01) and, more markedly, at 24 hours (P<0.01). Decreased bleeding after antifibrinolytic treatment was accompanied by reduced interleukin‐6 levels at 3 hours (P<0.05) and smaller lesion volume at 14 days (P<0.01). CM352 drastically reduced sensorimotor impairment (cylinder test) after ICH in rats at 24 hours (P<0.01) and 14 days (P<0.01). Similarly, it also attenuated neurological deficit (Bederson scale) at 24 hours (P<0.01) and 14 days (P<0.01). Interestingly, late (3 hours) CM352 administration also resulted in reduced lesion size and better functional outcome.Conclusions CM352, a new antifibrinolytic agent and matrix metalloproteinase inhibitor, effectively prevented hematoma growth and reduced lesion size in ICH in association with improved functional and neurological recovery.

Hematoma Expansion in Intracerebral Hemorrhage: An Update on Prediction and Treatment

“…A serials of preclinical researches of MMP inhibitors like CM352 ( 88 , 166 – 168 ), and neuroprotectors such as NXY-059 ( 169 , 170 ), NSP-116 ( 171 ), erythropoietin ( 172 ), valproic acid ( 173 ), memantine ( 174 ), curcumin ( 175 ), albumin ( 176 ), and tuftsin fragment 1-3 ( 177 ) have shed light on the treatment of HE. However, further studies to confirm the effect of CM352 and neuroprotectors are needed, since some pre-clinic medicines failed in clinical trials.…”

Head down tilt 15° in experimental intracerebral hemorrhage: a randomized noninferiority safety trial

“…A first limitation of our study is that functional outcome was limited to the first 24 h. However, our study was focused on safety and particularly on the risks of acute hematoma expansion and acute ICP changes associated with a brief application of HDT15°. Moreover, long‐term outcome is directly dependent on acute hematoma expansion, early hematoma volume, and early neurologic status in rats as in humans [21,22].…”

Inflammation, edema and poor outcome are associated with hyperthermia in hypertensive intracerebral hemorrhages

“…These findings support our previous data, where we found that a biomarker of the blood–brain barrier (matrix metalloproteinase‐9) was a mediator between hyperthermia and poor outcome in a heterogeneous population of patients with ICH . Recently, we reported an acute short‐term treatment with a new antifibrinolytic agent (CM352), which limits brain damage by reducing hematoma expansion leading to improved functional and neurological recovery in an ICH rat model .…”