myelin-basic-protein and Cerebellar-Diseases

Vigabatrin is the drug of choice in resistant epilepsy and infantile spasms. Ataxia, tremors, and abnormal gait have been frequently reported following its use indicating cerebellar involvement. This study aimed, for the first time, to investigate the involvement of necroptosis and apoptosis in the VG-induced cerebellar cell loss and the possible protective role of combined omega-3 and vitamin B12 supplementation. Fifty Sprague-Dawley adult male rats (160-200 g) were divided into equal five groups: the control group received normal saline, VG200 and VG400 groups received VG (200 mg or 400 mg/kg, respectively), VG200 + OB and VG400 + OB groups received combined VG (200 mg or 400 mg/kg, respectively), vitamin B12 (1 mg/kg), and omega-3 (1 g/kg). All medications were given daily by gavage for four weeks. Histopathological changes were examined in H&E and luxol fast blue (LFB) stained sections. Immunohistochemical staining for caspase-3 and receptor-interacting serine/threonine-protein kinase-1 (RIPK1) as well as quantitative real-time polymerase chain reaction (qRT-PCR) for myelin basic protein (MBP), caspase-3, and receptor-interacting serine/threonine-protein kinase-3 (RIPK3) genes were performed. VG caused a decrease in the granular layer thickness and Purkinje cell number, vacuolations, demyelination, suppression of MBP gene expression, and induction of caspases-3, RIPK1, and RIPK3 in a dose-related manner. Combined supplementation with B12 and omega-3 improved the cerebellar histology, increased MBP, and decreased apoptotic and necroptotic markers. In conclusion, VG-induced neuronal cell loss is dose-dependent and related to both apoptosis and necroptosis. This could either be ameliorated (in low-dose VG) or reduced (in high-dose VG) by combined supplementation with B12 and omega-3.

Topics: Animals; Anticonvulsants; Apoptosis; Caspase 3; Cerebellar Diseases; Dose-Response Relationship, Drug; Fatty Acids, Omega-3; Gene Expression Regulation; Male; Myelin Basic Protein; Necroptosis; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor-Interacting Protein Serine-Threonine Kinases; RNA, Messenger; Vigabatrin; Vitamin B 12

Normal human kidney contains a neutral endopeptidase that can degrade human myelin basic protein peptide 43-88. In the present study, renal homogenates prepared from postmortem tissue obtained from four persons with multiple sclerosis, two with amyotrophic lateral sclerosis, one each with olivopontocerebellar atrophy, subacute sclerosing panencephalitis, and Guillain-Barré syndrome, and four controls were analyzed for the enzymes present that degrade human myelin BP peptide 43-88. There was no evidence that the activity in renal tissue for degrading human BP peptide 43-88 is qualitatively different in persons with MS, other neurologic diseases, or controls. Gel filtration of digested peptide demonstrated the action of an endopeptidase capable of hydrolyzing BP peptide 43-88 into large fragments.

Topics: Adolescent; Adult; Aged; Amyotrophic Lateral Sclerosis; Cerebellar Diseases; Endopeptidases; Female; Humans; Kidney; Male; Middle Aged; Multiple Sclerosis; Myelin Basic Protein; Nervous System Diseases; Peptide Fragments; Polyradiculoneuropathy; Subacute Sclerosing Panencephalitis