Carbidopa-Based Modulation of the Functional Effect of the AAV2-hAADC Gene Therapy in 6-OHDA Lesioned Rats
نویسندگان
چکیده
Progressively blunted response to L-DOPA in Parkinson's disease (PD) is a critical factor that complicates long-term pharmacotherapy in view of the central importance of this drug in management of the PD-related motor disturbance. This phenomenon is likely due to progressive loss of one of the key enzymes involved in the biosynthetic pathway for dopamine in the basal ganglia: aromatic L-amino acid decarboxylase (AADC). We have developed a gene therapy based on an adeno-associated virus encoding human AADC (AAV2-hAADC) infused into the Parkinsonian striatum. Although no adverse clinical effects of the AAV2-hAADC gene therapy have been observed so far, the ability to more precisely regulate transgene expression or transgene product activity could be an important long-term safety feature. The present study was designed to define pharmacological regulation of the functional activity of AAV2-hAADC transgene product by manipulating L-DOPA and carbidopa (AADC inhibitor) administration in hemi-parkinsonian rats. Thirty days after unilateral striatal infusion of AAV2-hAADC, animals displayed circling behavior and acceleration of dopamine metabolism in the lesioned striatum after administration of a low dose of L-DOPA (5 mg/kg) co-administered with 1.25 mg/kg of carbidopa. This phenomenon was not observed in control AAV2-GFP-treated rats. Withdrawal of carbidopa from a daily L-DOPA regimen decreased the peripheral L-DOPA pool, resulting in almost total loss of L-DOPA-induced behavioral response in AAV2-hAADC rats and a significant decline in striatal dopamine turnover. The serum L-DOPA level correlated with the magnitude of circling behavior in AAV2-hAADC rats. Additionally, AADC activity in homogenates of lesioned striata transduced by AAV2-AADC was 10-fold higher when compared with AAV2-GFP-treated control striata, confirming functional transduction. Our data suggests that the pharmacological regulation of circulating L-DOPA might be effective in the controlling of function of AAV2-hAADC transgene product in PD gene therapy.
منابع مشابه
Preconditioning Effect of Aerobic Exercise with Vitamin D3 Intake on VEGF Levels in 6-OHDA-Lesioned Rat Model of Parkinson's Disease
Background and Objective: The purpose of this study was to investigate the preconditioning effect of aerobic exercise with vitamin D3 consumption on vascular endothelial growth factor (VEGF) level in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson’s disease. Materials and Methods: Forty-eight male rats weighing 250-300 g were randomly assigned to 6 groups: healthy control, Parkin...
متن کاملSleep deprivation disrupts striatal anti-apoptotic responses in 6-hydroxy dopamine-lesioned parkinsonian rats
Objective(s): The present study was conducted to examine the effect of sleep deprivation (SD) on the anti-apoptotic pathways in Parkinsonian rats. Materials and Methods: Male Wistar rats (n = 40) were assigned to four groups (10 animals each): sham surgery (Sham), 6-hydroxydopamine (6-OHDA)-lesioned (OH), 6-OHDA-lesioned plus grid control (OH+GC), 6-OHDA-lesioned plus SD (OH+SD). Parkinson’s di...
متن کاملNeuroprotection and restoration of the nigrostriatal dopaminergic system in 6-OHDA lesioned rat model of Parkinson's disease: Role of GDNF and TGF expressing Zuckerkandl's organ
Zuckerkandl’s organ (ZK) is an extra adrenal para-ganglion and has the ability to express glial cell line derived neurotrophic factor (GDNF) and transforming growth factor (TGF). It is also a source of dopamine and norepinephrine. In the present study, the neuroprotective and restorative potential of ZK was studied by transplanting it into the striatum of adult rats either before or after the i...
متن کاملNeuroprotection and restoration of the nigrostriatal dopaminergic system in 6-OHDA lesioned rat model of Parkinson's disease: Role of GDNF and TGF expressing Zuckerkandl's organ
Zuckerkandl’s organ (ZK) is an extra adrenal para-ganglion and has the ability to express glial cell line derived neurotrophic factor (GDNF) and transforming growth factor (TGF). It is also a source of dopamine and norepinephrine. In the present study, the neuroprotective and restorative potential of ZK was studied by transplanting it into the striatum of adult rats either before or after the i...
متن کاملThe Effect of Sesamin on Motor Asymmetry in Intrastriatal 6-Hydroxydopamine Rat Model of Parkinson's Disease
Background and Objective: Parkinson's disease (PD) is an age-related neurodegenerative disease with selective damage of dopaminergic neurons of the mesencephalon. L-dihydroxyphenylamine (L-DOPA) therapy is currently the gold standard maneuver for PD. Due to the protective, anti-inflammatory, and antioxidant effect of sesamin, this study was undertaken to assess dose-dependent effect of this age...
متن کامل