Cerebral blood flow regulation by nitric oxide in Alzheimer's disease.
Cerebral hypoperfusion due to impaired bioavailability of nitric oxide (NO) synthesized by endothelial nitric oxide synthase and neuronal nitric oxide synthase leads to cognitive decline and neurodegeneration in Alzheimer's disease (AD). Risk factors for endothelial dysfunction, such as inadequate lifestyle, cardiovascular/metabolic diseases, and aging, evokes cerebral hypoperfusion, impaired autoregulation, and increased production of amyloid-β peptides (Aβ) in association with vasculogenic memory loss and dementia. Decrease in parasympathetic nitrergic nerve activity also plays a role in cerebral hypoperfusion. Aβ is a functional obstacle to NO-mediated vasodilatation; therefore, it decreases cerebral blood flow. Generation of reactive oxygen species by Aβ is a major action in promoting NO degradation. Effective strategies for the prophylaxis or treatment of AD includes acetylcholinesterase inhibitors, drugs acting on the NO-cyclic GMP signaling pathway, antioxidants, peroxisome proliferator-activated receptor γ-agonists, and hydroxymethylglutaryl-CoA reductase inhibitors. Here our hypothesis about the mechanisms underlying the actions of acetylcholinesterase inhibitors in relation to NO-mediated cerebral blood flow is presented. Future detailed analyses of the relationship between cerebral blood flow regulation by constitutive NO and cognitive decline/neurodegeneration will provide clues for developing novel prophylactic measures and therapeutic means to alleviate AD.
Toyama Institute for Cardiovascular Pharmacology Research, Osaka, Japan. n.toda.toyamabldg@orion.ocn.ne.jp
Noboru
N
Toda
Tomio
T
Okamura
D000544:Alzheimer Disease / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D006801:Humans; D009569:Nitric Oxide / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014664:Vasodilation / Q000502:physiology
D009569:Nitric Oxide