title: 2-BFI attenuates experimental autoimmune encephalomyelitis-induced spinal cord injury with enhanced B-CK, CaATPase, but reduced calpain activity.
abstract: The lack of disease-modifying pharmacological agents for effective treatment of multiple sclerosis (MS) still represents a large and urgent unmet medical need. Our previous studies showed that ligands to type 2 imidazoline receptors (I(2)R) were effective in protecting spinal cord injury caused by experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In this study, we further examined the protective property of a very selective ligand of I(2)R, 2-(2-benzofuranyl) 2-imidazoline (2-BFI) against EAE. Importantly, a mechanism of 2-BFI-mediated protection was investigated which possibly involves an I(2)R binding protein, brain-creatine kinase (B-CK), as well as CaATPase and calpain. The enzymatic activity of B-CK and CaATPase was significantly reduced in EAE injured spinal cord. Reduction of B-CK activity in EAE spinal cord may lead to energy reduction and dysfunction in cellular calcium homeostasis. Increased intracellular calcium evokes elevation of calpain activity occurring in EAE spinal cord which causes further tissue damage. Indeed, EAE injured spinal cord showed significant reduction in CaATPase and increase calpain activities. Remarkably, spinal cord tissue from mice treated daily with 2-BFI during the progression of EAE significantly restored B-CK and CaATPase enzymatic activities and showed no induction in calpain activity. Moreover, EAE spinal cord from 2-BFI treated mice also demonstrated better preservation of myelin; reduced axonal injury, as evidenced by the lower level of β-APP expression, and above all, highly improved neurobehavioral scores (p<0.01; n=10). These findings suggest that 2-BFI can be further developed as a therapeutic drug for MS treatment.
authors.affiliation: Department of Neurology, The First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, No. 2 Fuxue Lane, Wenzhou City, Zhejiang Province 325000, PR China.
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.forename: Zhao-Wei
authors.initials: ZW
authors.lastname: Wang
authors.forename: Fu-Hong
authors.initials: FH
authors.lastname: Lin
authors.forename: Zhao
authors.initials: Z
authors.lastname: Han
authors.forename: Sheng-Tao
authors.initials: ST
authors.lastname: Hou
authors.forename: Rong-Yuan
authors.initials: RY
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D001572:Benzofurans / Q000627:therapeutic use*; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis; D002154:Calpain / Q000037:antagonists & inhibitors; D052276:Creatine Kinase, BB Form / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D005260:Female; D007093:Imidazoles / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000201:enzymology; D013119:Spinal Cord Injuries / Q000150:complications / Q000201:enzymology
chemical_list: D001572:Benzofurans; D007093:Imidazoles; C103723:2-(2-benzofuranyl)-2-imidazoline; D052276:Creatine Kinase, BB Form; D002154:Calpain; D000252:Calcium-Transporting ATPases