Abstract
Background/AimsSince the degeneration of the nigrostriatal dopaminergic pathway in Parkinson’s disease (PD) is associated with the inflammation process and decreased levels of cyclic nucleotides, inhibition of up-regulated cyclic nucleotide phosphodiesterases (PDEs) appears to be a promising therapeutic strategy. We used ibudilast (IBD), a non-selective PDE3,4,10,11 inhibitor, due to the abundant PDE 4 and 10 expression in the striatum. The present study for the first time examined the efficacy of IBD in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD.MethodsIBD [0, 20, 30, 40, or 50 mg/kg] was injected b.i.d. subcutaneously for nine days to three-month-old male C57Bl/10Tar mice, beginning two days prior to MPTP (60 mg/kg) intoxication. High-pressure liquid chromatography, Western blot analysis, and real time RT-PCR methods were applied.ResultsOur study demonstrated that chronic administration of IBD attenuated astroglial reactivity and increased glial cell-derived neurotrophic factor (GDNF) production in the striatum. Moreover, IBD reduced TNF-α, IL-6, and IL-1β expression.ConclusionIBD had a well-defined effect on astroglial activation in the mouse model of PD; however, there was no protective effect in the acute phase of injury. Diminished inflammation and an increased level of GDNF may provide a better outcome in the later stages of neurodegeneration.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 2% of the population over 65 years of age [1]
Our study demonstrated that chronic administration of IBD attenuated astroglial reactivity and increased glial cell-derived neurotrophic factor (GDNF) production in the striatum
Experimental and clinical studies have demonstrated that the cyclic nucleotide phosphodiesterase (PDE) inhibitors may be useful in treating neuroinflammatory disorders
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting about 2% of the population over 65 years of age [1]. The currently available treatments improve some symptoms of the disease; they have sub-optimal efficacy that is related to the duration of the disease. A neuroprotective or disease modifying treatment is still needed [2, 3]. Since chronic neuroinflammation is associated with the pathogenesis of PD, the neuroinflammatory signaling pathways in the central nervous system (CNS) are of interest as potential pharmacotherapy targets [4]. Several candidate drugs directed at these targets have reached clinical trials but, none were effective. Experimental and clinical studies have demonstrated that the cyclic nucleotide phosphodiesterase (PDE) inhibitors may be useful in treating neuroinflammatory disorders
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