Homocysteine increases the production of asymmetric dimethylarginine in cultured neurons.
Increased circulating concentrations of homocysteine may be a risk factor for Alzheimer's disease and cognitive dysfunction in normal aging. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (NOS). ADMA is metabolized in neurons by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). Nitric oxide plays an important role in synaptic events involved in learning and memory. We determined the effect of L-homocysteine on ADMA accumulation and nitric oxide production in cultured rat neuronal granule cells. The incubation of neuronal granule cells with L-homocysteine for 24 hr caused a dose-dependent accumulation of ADMA and a dose-dependent decrease in nitric oxide production. The addition of the sulfhydryl antioxidant pyrrolidine dithiocarbamate (PDTC) attenuated the effect of homocysteine on ADMA accumulation and nitric oxide production. DDAH activity had a decreasing dose-response relationship with increasing L-homocysteine concentrations. The addition of PDTC caused a dose-dependent increase in DDAH activity. The addition of the N-methyl-D-aspartate receptor antagonists (+/-)-2-amino-5-phosphopentanoic acid and 7-chlorokynurenate had no effect on the inhibition of DDAH by homocysteine. It is concluded that L-homocysteine inhibits DDAH activity, thereby causing ADMA accumulation and decreasing nitric oxide production in cultured neurons. The protective effect of PDTC suggests that L-homocysteine inactivates DDAH in neurons by reacting with the cysteine residue in its active site. The preservation of DDAH activity and the reduction of ADMA accumulation in neurons may be a new strategy for the treatment of Alzheimer's disease and cognitive impairment in normal aging.
Selley
Michael L
ML
Angiogen Pharmaceuticals Pty. Ltd., Sydney, New South Wales, Australia. mlselley@angiogen.com.au
D000544:Alzheimer Disease / Q000378:metabolism; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000096:biosynthesis*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D013859:Thiocarbamates / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D000975:Antioxidants; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D013859:Thiocarbamates; C487735:dimethylarginine; D006710:Homocysteine; C066229:prolinedithiocarbamate; D009569:Nitric Oxide; D001120:Arginine; D011392:Proline; D019001:Nitric Oxide Synthase; D000581:Amidohydrolases; C059999:dimethylargininase