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Neuroprotective Effects of MAGL (Monoacylglycerol Lipase) Inhibitors in Experimental Ischemic Stroke.
Choi, Sang-Ho; Arai, Allison L; Mou, Yongshan; Kang, Byeongteck; Yen, Cecil Chern-Chyi; Hallenbeck, John; Silva, Afonso C.
Afiliação
  • Choi SH; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
  • Arai AL; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
  • Mou Y; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
  • Kang B; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
  • Yen CC; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
  • Hallenbeck J; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
  • Silva AC; From the Cerebral Microcirculation Section, Laboratory of Functional and Molecular Imaging (S.-H.C., A.A., C.C.-C.Y., A.C.S.); National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (Y.M., J.H.); and College of Veterinary Medicine, Chungbuk National Univ
Stroke ; 49(3): 718-726, 2018 03.
Article em En | MEDLINE | ID: mdl-29440474
ABSTRACT
BACKGROUND AND

PURPOSE:

MAGL (monoacylglycerol lipase) is an enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol and regulates the production of arachidonic acid and prostaglandins-substances that mediate tissue inflammatory response. Here, we have studied the effects of the selective MAGL inhibitors JZL184 and MJN110 and their underlying molecular mechanisms on 3 different experimental models of focal cerebral ischemia.

METHODS:

SHR (spontaneously hypertensive rats) and normotensive WKY (Wistar Kyoto) rats were subject to an intracortical injection of the potent vasoconstrictor endothelin-1, permanent occlusion of a distal segment of the middle cerebral artery via craniectomy, or transient occlusion of the middle cerebral artery by the intraluminal suture method. JZL184 or MJN110 was administered 60 minutes after focal cerebral ischemia. Infarct volumes, hemispheric swelling, and functional outcomes were assessed between days 1 to 28 by magnetic resonance imaging, histology, and behavioral tests.

RESULTS:

Pharmacological inhibition of MAGL significantly attenuated infarct volume and hemispheric swelling. MAGL inhibition also ameliorated sensorimotor deficits, suppressed inflammatory response, and decreased the number of degenerating neurons. These beneficial effects of MAGL inhibition were not fully abrogated by selective antagonists of cannabinoid receptors, indicating that the anti-inflammatory effects are caused by inhibition of eicosanoid production rather than by activation of cannabinoid receptors.

CONCLUSIONS:

Our results suggest that MAGL may contribute to the pathophysiology of focal cerebral ischemia and is thus a promising therapeutic target for the treatment of ischemic stroke.
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Piperidinas / Succinimidas / Carbamatos / Isquemia Encefálica / Fármacos Neuroprotetores / Acidente Vascular Cerebral / Inibidores Enzimáticos / Benzodioxóis / Monoacilglicerol Lipases Limite: Animals Idioma: En Revista: Stroke Ano de publicação: 2018 Tipo de documento: Article
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Piperidinas / Succinimidas / Carbamatos / Isquemia Encefálica / Fármacos Neuroprotetores / Acidente Vascular Cerebral / Inibidores Enzimáticos / Benzodioxóis / Monoacilglicerol Lipases Limite: Animals Idioma: En Revista: Stroke Ano de publicação: 2018 Tipo de documento: Article