The effect of subchronic, intermittent L-DOPA treatment on neuronal nitric oxide synthase and soluble guanylyl cyclase expression and activity in the striatum and midbrain of normal and MPTP-treated mice.
We have investigated the effects of low (10 mg/kg) and high (100 mg/kg) doses of L-DOPA on the expression and activity of neuronal nitric oxide synthase (nNOS) and guanylyl cyclase (GC) in the striatum and midbrain of mice. L-DOPA was administered subchronically for 11 days (beginning 3 days after last MPTP/NaCl injection) or for 14 days (with dosing started immediately following the last MPTP/NaCl injection). Adult mice received three intraperitoneal (i.p.) injections of physiological saline or MPTP at 2h intervals (total dose of 40 mg/kg). Normal and MPTP-injected mice were treated twice a day for 11 or 14 days with low (10/2.5 mg/kg bw) or high (100/25mg/kg bw) doses of L-DOPA/benserazide. The present study indicates that several days of treatment with L-DOPA does not affect MPTP-activation of the nNOS/sGC/cGMP pathway or the neurodegenerative processes that occur in the striatum and midbrain of mice. In normal mice, L-DOPA upregulates the expression and activity of nNOS and GC to levels found in MPTP-injected mice. Due to upregulation of nNOS and GC, cGMP levels in the mouse striatum and midbrain are also elevated, however, significantly lower in mice administrated with low dose of L-DOPA. In both investigated brain regions of normal mice cGMP-dependent PDEs activities were elevated after low dose administration of L-DOPA, but no change in PDEs activities has been detected in MPTP and high L-DOPA-injected mice as compared to control values. The enhancement of nNOS mRNA and GCbeta1 mRNA levels were generated by both doses of L-DOPA, given in a time-dependent fashion. L-DOPA-injected for 11 or 14 days caused a decrease in TH protein levels in the striatum and midbrain, respectively; this result was noted irrespective of dose. L-DOPA therapy did not prevent the MPTP-induced decrease in TH protein levels in either investigated brain region.
Chalimoniuk
M
M
Department of Cellular Signaling, Medical Research Center, Polish Academy of Sciences, 5 Pawińskiego St., 02-106 Warsaw, Poland. mchalim@yahoo.com
Langfort
J
J
D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D006162:Guanylate Cyclase / Q000096:biosynthesis*; D007150:Immunohistochemistry; D007980:Levodopa / Q000494:pharmacology*; D020267:MPTP Poisoning / Q000201:enzymology*; D008636:Mesencephalon / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D007980:Levodopa; D052248:Nitric Oxide Synthase Type I; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D004298:Dopamine