title: Neuronal Ca2+ disregulation in diabetes mellitus.
abstract: The Ca(2+) hypothesis of brain ageing and dementia may account for part of the available data on the pathogenesis of dementia and certain neurodegenerative disorders. The hypothesis proposes that disturbances in the homeostasis of neuronal cytosolic free Ca(2+) are part of a final common pathway, ultimately leading to neuronal dysfunction and cell death. The hypothesis also proposes that a small change in cytosolic free Ca(2+) sustained over a long period of time will result in similar damage as a large change over a short period. Diabetes mellitus is associated with neurological complications in the peripheral and central nervous system, as reflected in peripheral neuropathy, modest cognitive impairments and an increased risk of dementia. In animal models of diabetes, learning impairments are associated with alterations in Ca(2+) -dependent forms of hippocampal synaptic plasticity. Disturbances in the homeostasis of cytosolic free Ca(2+) may present a final common pathway in the multifactorial pathogenesis of neurological complications of diabetes, which involves vascular changes, oxidative stress, and non-enzymatic protein glycation. In line with the Ca(2+) hypothesis of neurodegenerative disorders, a prolonged, small increase in basal cytosolic Ca(2+) levels indeed exists in sensory neurones of diabetic animals. In addition, Ca(2+) dynamics are affected. Ca(2+) channel blockers, such as nimodipine, have been shown to improve experimental peripheral neuropathy, through a vascular mechanism, possibly in combination with direct neuronal effects. Preliminary studies indicate that nimodipine may also improve Ca(2+)-dependent forms of synaptic plasticity in the hippocampus of diabetic rats.
authors.affiliation: Department of Medical Pharmacology of the Rudolf Magnus Institute for Neuroscience, University Medical Centre, Utrecht, The Netherlands. G.J.Biessels@med.uu.nl
authors.forename: Geert Jan
authors.initials: GJ
authors.lastname: Biessels
authors.forename: Mariël P
authors.initials: MP
authors.lastname: ter Laak
authors.forename: Frank P T
authors.initials: FP
authors.lastname: Hamers
authors.forename: Willem Hendrik
authors.initials: WH
authors.lastname: Gispen
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000209:etiology; D006706:Homeostasis; D006801:Humans; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*
chemical_list: D002121:Calcium Channel Blockers; D002118:Calcium