nitroarginine and Parkinson-Disease

The development of new therapeutics for the treatment of neurodegenerative pathophysiologies currently stands at a crossroads. This presents an opportunity to transition future drug discovery efforts to target disease modification, an area in which much still remains unknown. In this Perspective we examine recent progress in the areas of neurodegenerative drug discovery, focusing on some of the most common targets and mechanisms: N-methyl-d-aspartic acid (NMDA) receptors, voltage gated calcium channels (VGCCs), neuronal nitric oxide synthase (nNOS), oxidative stress from reactive oxygen species, and protein aggregation. These represent the key players identified in neurodegeneration and are part of a complex, intertwined signaling cascade. The synergistic delivery of two or more compounds directed against these targets, along with the design of small molecules with multiple modes of action, should be explored in pursuit of more effective clinical treatments for neurodegenerative diseases.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Antioxidants; Calcium Channels; Drug Combinations; Drug Design; Humans; Huntington Disease; Neurodegenerative Diseases; Nitric Oxide Synthase Type I; Oxidative Stress; Parkinson Disease; Protein Folding; Protein Structure, Quaternary; Proteostasis Deficiencies; Receptors, N-Methyl-D-Aspartate

Parkinson's disease (PD) is a common neurodegenerative disorder which is mostly sporadic but familial-linked PD (FPD) cases have also been found. The first reported gene mutation that linked to PD is α-synuclein (α-syn). Studies have shown that mutations, increased expression or abnormal processing of α-syn can contribute to PD, but it is believed that multiple mechanisms are involved. One of the contributing factors is post-translational modification (PTM), such as phosphorylation of α-syn at serine 129 by G-protein-coupled receptor kinases (GRKs) and casein kinase 2α (CK2α). Another known important contributing factor to PD pathogenesis is oxidative and nitrosative stress. In this study, we found that GRK6 and CK2α can be S-nitrosylated by nitric oxide (NO) both in vitro and in vivo. S-nitrosylation of GRK6 and CK2α enhanced their kinase activity towards the phosphorylation of α-syn at S129. In an A53T α-syn transgenic mouse model of PD, we found that increased GRK6 and CK2α S-nitrosylation were observed in an age dependent manner and it was associated with an increased level of pSer129 α-syn. Treatment of A53T α-syn transgenic mice with Nω-Nitro-L-arginine (L-NNA) significantly reduced the S-nitrosylation of GRK6 and CK2α in the brain. Finally, deletion of neuronal nitric oxide synthase (nNOS) in A53T α-syn transgenic mice reduced the levels of pSer129 α-syn and α-syn in an age dependent manner. Our results provide a novel mechanism of how NO through S-nitrosylation of GRK6 and CK2α can enhance the phosphorylation of pSer129 α-syn in an animal model of PD.

Topics: Age Factors; alpha-Synuclein; Animals; Casein Kinase II; Disease Models, Animal; G-Protein-Coupled Receptor Kinases; Gene Deletion; HEK293 Cells; Humans; Mice; Mice, Transgenic; Mutation; Nitric Oxide; Nitric Oxide Synthase Type I; Nitroarginine; Nitrosative Stress; Parkinson Disease; Phosphorylation; Serine

Chronic L-DOPA pharmacotherapy in Parkinson's disease is often accompanied by the development of abnormal and excessive movements known as L-DOPA-induced dyskinesia. Rats with 6-hydroxydopamine lesion of dopaminergic neurons chronically treated with L-DOPA develop a rodent analog of this dyskinesia characterized by severe axial, limb, locomotor and orofacial abnormal involuntary movements. While the mechanisms by which these effects occur are not clear, they may involve the nitric oxide system. In the present study we investigate if nitric oxide synthase inhibitors can prevent dyskinesias induced by repeated administration of L-DOPA in rats with unilateral 6-hydroxydopamine lesion. Chronic L-DOPA (high fixed dose, 100 mg/kg; low escalating dose, 10-30 mg/kg) treatment induced progressive dyskinesia changes. Two nitric oxide synthase inhibitors, 7-nitroindazole (1-30 mg/kg) and NG-nitro-L-arginine (50 mg/kg), given 30 min before L-DOPA, attenuate dyskinesia. 7-Nitroindazolee also improved motor performance of these animals in the rota-rod test. These results suggest the possibility that nitric oxide synthase inhibitors may be useful to treat L-DOPA-induced dyskinesia.

Topics: Animals; Antiparkinson Agents; Corpus Striatum; Disease Models, Animal; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Indazoles; Levodopa; Male; Motor Activity; Nitric Oxide Synthase; Nitroarginine; Oxidopamine; Parkinson Disease; Rats; Rats, Wistar; Substantia Nigra

Nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine (NNLA) produced dose-dependent, long-lasting catalepsy in rats, the effect being attenuated by NO donors L-arginine and molsidomine. Catalepsy induced by haloperidol (0.4 mg/kg i.p.), D2 receptor antagonist, was reduced dose-dependently by molsidomine (10.0-100.0 mg/kg) and by L-arginine at a dose of 100.0 mg/kg. Low, non-cataleptic doses of NNLA (0.1 mg/kg) and haloperidol (0.1 mg/kg) given in combination produced a marked and long-lasting catalepsy. The results suggest that NO plays a role in NNLA-induced catalepsy as well as in catalepsy elicited by haloperidol.

Topics: Animals; Arginine; Catalepsy; Disease Models, Animal; Haloperidol; Male; Molsidomine; Nitric Oxide Synthase; Nitroarginine; Parkinson Disease; Rats; Rats, Wistar; Vasodilator Agents