Norharman-induced motoric impairment in mice: neurodegeneration and glial activation in substantia nigra.
The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.
Ostergren
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Department of Pharmaceutical Biosciences, Psychiatry Ulleraker, Uppsala University, Uppsala, Sweden.
Fredriksson
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Brittebo
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EB
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002243:Carbolines; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005452:Fluoresceins; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000503:physiopathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000139:chemically induced* / Q000503:physiopathology; D006247:Harmine / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000503:physiopathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity; D009930:Organic Chemicals; D016716:PC12 Cells; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000503:physiopathology; D051381:Rats; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
D002243:Carbolines; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D009498:Neurotoxins; D009930:Organic Chemicals; C435731:fluoro jade; D006247:Harmine; C010262:norharman; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases