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 2 h 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 (100/25 mg/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 GCβ1 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.