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Clomethiazole protects against hemineglect in a primate model of stroke
J W Marshall1, A J Cross, D M Jackson
1MRC Comparative Cognition Team, Department of Experimental Psychology, University of Cambridge, Cambridge, United Kingdom. jwbm2@cus.cam.ac.uk
Abstract:
Permanent occlusion of the M1 segment of the middle cerebral artery (pMCAO) in the marmoset, a New World species of monkey, produces unilateral functional deficits, including motor neglect with the contralesional arm and contralesional spatial hemineglect. In this study we examined whether clomethiazole, a drug which modulates the gamma-aminobutyric acid(A) receptor, reduced the severity of the hemineglect and other deficits in this primate model of stroke. Nine monkeys received pMCAO; 1 h later four of the nine were administered clomethiazole by intraperitoneal injection and subcutaneous implantation of osmotic mini-pumps, which released clomethiazole for 48 h. The monkeys had been trained and tested on a number of behavioral tasks prior to surgery and were re-tested 3 and 10 weeks later. Three weeks after pMCAO, monkeys treated with clomethiazole had a significantly reduced degree of spatial neglect compared to untreated controls. Clomethiazole was not effective against the severe contralesional motor impairment in the current study, although it ameliorated a somewhat less severe motor deficit in a previous study in which the more distal, M2 segment of the middle cerebral artery had been occluded. Postmortem analysis of the brains showed that clomethiazole treatment had significantly reduced the area of damage in part of the parietal cortex. These data suggest that clomethiazole may reduce the neglect that can be a debilitating consequence of right-sided stroke in man.
Insights
Clomethiazole, a drug modulating GABA(A) receptors, significantly reduced spatial neglect in a marmoset stroke model. While not improving motor deficits, it lessened brain damage, suggesting potential for treating stroke-related neglect in humans.
Area of Science:
- Neuroscience
- Pharmacology
- Primate Models of Stroke
Background:
- Middle cerebral artery occlusion (MCAO) in marmosets causes functional deficits like motor and spatial neglect.
- Clomethiazole is a drug that modulates gamma-aminobutyric acid(A) receptors.
Purpose of the Study:
- To investigate if clomethiazole reduces hemineglect and other deficits in a primate stroke model.
- To assess clomethiazole's efficacy in mitigating stroke-induced brain damage and functional impairments.
Main Methods:
- Permanent M1 segment of the middle cerebral artery occlusion (pMCAO) was induced in nine marmosets.
- Four monkeys received clomethiazole treatment via injection and osmotic mini-pumps for 48 hours.
- Behavioral tasks were administered pre-surgery and at 3 and 10 weeks post-surgery; brain damage was analyzed postmortem.
Main Results:
- Clomethiazole treatment significantly reduced spatial neglect severity at 3 weeks post-pMCAO compared to controls.
- The drug did not improve severe contralesional motor impairment but showed efficacy in a prior M2 occlusion model.
- Postmortem brain analysis revealed clomethiazole significantly reduced damage in parts of the parietal cortex.
Conclusions:
- Clomethiazole demonstrates potential in reducing spatial neglect following stroke.
- The drug's efficacy may be dependent on stroke severity and location.
- These findings suggest clomethiazole could be a therapeutic option for managing debilitating neglect symptoms in human stroke patients.