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{"project":"2_test","denotations":[{"id":"22577256-11124893-67984300","span":{"begin":219,"end":221},"obj":"11124893"},{"id":"22577256-21185368-67984301","span":{"begin":253,"end":256},"obj":"21185368"},{"id":"22577256-16958586-67984302","span":{"begin":1050,"end":1053},"obj":"16958586"},{"id":"22577256-7507781-67984303","span":{"begin":2201,"end":2204},"obj":"7507781"},{"id":"22577256-20116408-67984303","span":{"begin":2201,"end":2204},"obj":"20116408"},{"id":"22577256-7530937-67984303","span":{"begin":2201,"end":2204},"obj":"7530937"},{"id":"22577256-11423083-67984304","span":{"begin":2224,"end":2227},"obj":"11423083"},{"id":"22577256-12623224-67984305","span":{"begin":2329,"end":2332},"obj":"12623224"},{"id":"22577256-8711808-67984306","span":{"begin":2593,"end":2596},"obj":"8711808"},{"id":"22577256-21132259-67984307","span":{"begin":3481,"end":3484},"obj":"21132259"},{"id":"22577256-17855475-67984308","span":{"begin":4305,"end":4308},"obj":"17855475"},{"id":"22577256-16703907-67984309","span":{"begin":5401,"end":5404},"obj":"16703907"},{"id":"22577256-21044082-67984310","span":{"begin":5758,"end":5761},"obj":"21044082"},{"id":"22577256-11489548-67984311","span":{"begin":6139,"end":6142},"obj":"11489548"},{"id":"22577256-15789754-67984312","span":{"begin":6171,"end":6174},"obj":"15789754"},{"id":"22577256-11085889-67984313","span":{"begin":7296,"end":7299},"obj":"11085889"},{"id":"22577256-14690537-67984314","span":{"begin":7769,"end":7772},"obj":"14690537"},{"id":"22577256-17254027-67984315","span":{"begin":7774,"end":7777},"obj":"17254027"},{"id":"22577256-14690537-67984316","span":{"begin":8307,"end":8310},"obj":"14690537"},{"id":"22577256-17976742-67984317","span":{"begin":8312,"end":8315},"obj":"17976742"}],"text":"6. Inducible Nitric Oxide Synthase Inhibitors and Experimental Models of PD\nIt is well documented that experimental PD models using various toxins and MPTP-induced dopaminergic degeneration express high levels of iNOS [37, 120]. Recently, Broom et al. [121] reported a selective iNOS inhibitor, GW274150 ([2-[(1-iminoethyl) amino] ethyl]-L-homocysteine, Figure 4(a)) showing a potent role in the pathogenesis of PD. They indicated that 6-OHDA administration produced an increased number of cells expressing iNOS and was also associated with increased microglial activation. GW274150 treatment (3, 10, and 30 mg/kg) orally twice daily for 7 consecutive days leads to a suppression of iNOS expression and the inflammatory response in the 6-OHDA model of PD and was neuroprotective but at a narrow therapeutic range. The findings from this paper support the concept that NO has a detrimental effect on dopaminergic neurons and that modulation of the inflammatory response may be a valid neuroprotective therapeutic approach in treating PD.\nGahm et al. [122] reported that L-N-iminoethyl-lysine (L-NIL, Figure 4(b)), a selective iNOS inhibitor, appeared to protect the injured brain by limiting OONO− formation. Their study analyzed a variety of parameters including neuronal degeneration, survival, cellular apoptosis, and formation of nitrotyrosine following traumatic brain injury (TBI). L-NIL significantly reduced iNOS activity in animals injured by brain contusion. Moreover, neuronal degeneration and NT immunoreactivity significantly reduced at 24 h. Neuronal survival was unchanged at 24 h but increased at 6 days in L-NIL-treated animals. Cellular apoptosis of mononuclear phagocytes (ED-1) and neuron (NeuN) positive cells were significantly reduced following L-NIL treatment 6 days after trauma. These findings also strongly support a putative harmful role of iNOS induction early after TBI and the neuroprotective role of L-NIL in neurodegenerative diseases such as PD.\nThe neuroprotective actions of aminoguanidine (AG, Figure 4(c)) have long been studied. Several authors reported that the selective inhibition of iNOS is one of the major mechanisms by which AG exerts its neuroprotection [123–125]. Cash et al. [126] reported the neuroprotective effects of AG on transient focal ischemia in the rat brain. Lu et al. [127] proposed the neuroprotective action of AG by combined magnetic resonance imaging and histopathologic and functional analysis after lateral fluid-percussive brain injury in rats. The cerebroprotective effect of AG in a rodent model of stroke was also studied [128]. In a recent report [129], the effectiveness of AG was studied in modulating the toxicity of aluminum chloride on the nitrite levels, malondialdehyde concentration, reduced glutathione content, and cytochrome c oxidase activity in Wistar rats and confirmed that the inhibition of iNOS was responsible for this action. All these studies have concluded that the potent inhibition of iNOS activity was partly responsible for neuroprotection and AG can be further developed in the prevention of various CNS disorders including PD.\nQuercetin (Figure 4(d)), a major flavonoid naturally occurring in plants, deserves attention because of its beneficial effects observed in various in vitro and in vivo neural damage models. Quercetin significantly exerted a neuroprotective effect through inhibition of the iNOS/NO system and proinflammation gene expression in PC12 cells and in Zebrafish [130]. The selective dopaminergic neurotoxin 6-OHDA was used to induce neural damage in PC12 cells and Zebrafish. Pretreatment with quercetin offered neuroprotection against 6-OHDA-induced PC12 apoptotic cell death and dopaminergic neuronal loss in Zebrafish. A mechanistic study revealed that quercetin could inhibit NO overproduction and iNOS overexpression in PC12 cells and downregulates the overexpression of proinflammatory genes suggesting that role of quercetin in neuroprotection leading to its development as an effective therapeutic agent for the treatment neurodegenerative diseases including PD.\nThe neuroprotective effects of glyceryl nonivamide (GLNVA, Figure 5(a)), a vanilloid receptor (VR) agonist on activated microglia and 6-OHDA-induced neurotoxicity in dopaminergic SH-SY5Y cells were studied recently [131]. The authors revealed that GLNVA decreased LPS-activated microglia-induced overexpression of neuronal nitric-oxide synthase and gp91phox on SH-SY5Y cells. GLNVA (1, 10, 100 μM) for 24 h diminished LPS-induced NO production, overexpression of iNOS, and intracellular reactive oxygen species in activated microglia. 6-OHDA-induced overexpression of nNOS, iNOS, COX-2, and gp91phox were also reduced by GLNVA in SH-SY5Y cells. The neuroprotective effects of GLNVA are mediated, at least in part, by decreasing the inflammation- and oxidative-stress-associated factors induced by microglia and 6-OHDA.\nThe neuroprotective effects of exogenous agmatine, a guanidinium compound (Figure 5(b)), were investigated in experimental spinal cord injury (SCI). Agmatine is a neurotransmitter—neuromodulator with both N-methyl-d-aspartate receptor (NMDAR)—antagonizing and NO synthase-inhibiting activities. Agmatine administration following SCI was shown to reduce NO levels significantly and suggested that this drug may be helpful in the treatment of patients with neurodegeneration especially in SCIs [132]. In a recent study, the effects of agmatine on cell injury induced by rotenone commonly used in establishing in vivo and in vitro models of PD in a human-derived dopaminergic SH-SY5Y cell line were shown. Agmatine dose-dependently suppressed rotenone-induced cellular injury through a reduction of oxidative stress, by protecting dopaminergic neurons [133].\nWogonin (5, 7-dihydroxy-8-methoxyflavone, Figure 5(c)), an active component originated from the root of Scutellaria baicalensis, has been reported to possess antioxidant and anti-inflammatory properties. Wogonin (5, 20, 50 mM) inhibited inflammatory activation of cultured brain microglia by diminishing LPS-induced NO production via suppressing iNOS induction in microglia [134]. Furthermore, Chun et al. [135] reported the inhibitory activities of wogonin derivatives on LPS-induced NO production in BV-2 microglial cells and on H2O2-induced neuronal cell death in SH-SY5Y cells. Wogonin and its derivatives ranging between 5, 10, 20, and 40 μM concentration decreased the production of NO and inflammatory cytokines owing to their potential role in mitigating neuroinflammation seen in PD.\n2-Phenyl-1,2-benzisoselenazole-3(2H)-one (ebselen), a seleno organic compound and a strong ONOO− cleansing agent (Figure 5(d)), possesses antioxidant and anti-inflammatory properties and is now under clinical trials for the treatment of ischemic stroke. Earlier reports indicated that ebselen can also preferentially inhibit the activity of inducible nitric oxide (NO) synthase within a certain concentration range [136]. Ebselen prevented both neuronal loss and clinical symptoms in a primate MPTP model of PD. Ebselen (10 μM) also prevented peroxide radical overproduction induced by serum withdrawal in cultured PC12 cells and hydroxyl radical generation induced by the mitochondrial toxin, MPP+, in an in vivo system in the rat brain [137]. The authors indicated that ebselen inhibited the free radical production and may be useful as preventive treatment in PD.\nPioglitazone, a PPARgamma agonist (Figure 6(a)), was reported to protect mice from MPTP-induced dopaminergic cell loss, glial activation, and loss of catecholamines in the striatum. In addition, pioglitazone (10 μM) provided neuroprotective properties to substantia nigra dopaminergic neurons in LPS-induced PD models both in vivo and in vitro [138, 139]. In mice treated with pioglitazone, there was reduced activation of microglia, reduced induction of iNOS-positive cells and less glial fibrillary acidic protein positive cells in both the striatum and substantia nigra pars compacta. A comprehensive mechanistic study revealed that pioglitazone-mediated neuroprotection involves inhibition of microglial activation and decreased expression and activity of iNOS and may offer a treatment opportunity in PD to slow the progression of disease that is mediated by neuroinflammation [138, 140].\nRecently, the antidepressant paroxetine (Figure 6(b)) was reported to promote the survival of nigrostriatal dopaminergic neurons in the MPTP mouse model of PD. Treatment with paroxetine (10 mg/kg body weight, equivalent to 0.2–0.25 mg/day) into the peritoneum for 6 days, beginning at 12 h after last MPTP injection, prevented the degeneration of nigrostriatal DA neurons, increased striatal dopamine levels, and improved motor function. The authors indicated that the neuroprotection afforded by paroxetine may partly be associated with the suppression of iNOS in activated microglia [141].\nDuring the last five years, several novel compounds that selectively inhibit iNOS expression have been patented. Thomas et al. [142] claimed the usefulness of imidazopyridine derivatives (Figure 6(c)) as iNOS inhibitors. They found the novel 7-amino-3, 4, 5, 6, tetrahydro-2H-azepin-2-yl-substituted imidazopyridine derivatives have valuable pharmacological properties which make them commercially utilizable. They are selective inhibitors of the enzyme iNOS. On account of their iNOS-inhibiting properties, the compounds according to the invention can be employed in human, veterinary medicine, and therapeutics, where an excess of NO or O2 − is involved due to iNOS activation. They can be used without limitation for the treatment and prophylaxis of various neuroinflammatory and neurodegenerative diseases including PD [142].\nA patent has also been obtained by Sharon et al. [143] on a few novel coumarins (Figure 6(d)) for their use as inhibitors of iNOS. Their study reveals that the compounds synthesized from their invention can be used for various neurodegenerative diseases including PD. \nRecently, Tadayoshi et al. [144] filed a patent for a sense oligonucleotide with sequence complementary to a single-stranded RNA (antisense transcript) with sequence complementary to mRNA of the iNOS gene in order to control expression of iNOS. The authors reveal that the proposed invention can control the expression of iNOS and can be useful for biological defense in ameliorating diseases related to excessive production of NO, such as neuroinflammation.\nTheopederin and derivatives (Figure 6(e)) are marine natural substances isolated and purified from Porifera species. In a recent patent, a pharmaceutical and health food preparation containing theopederin derivatives as active constituents was claimed by Heonjoong and Hyun-Sil [145]. The authors claim that these derivatives selectively inhibit the excessive generation of NO and iNOS activation and are useful to treat and/or prevent various diseases including autoimmune diseases, inflammatory diseases, multiple sclerosis, and neurodegeneration.\nThere has also been a patent filed by Singh [146] on the exemplary compound lovastatin, which is a sodium salt of phenylacetic acid, FPT inhibitor II, N-acetyl cysteine, and cyclic AMP, selectively inhibit the iNOS activation in LPS-stimulated microglial cells, and can be used for the treatment of various neuroinflammatory diseases.\nThe role of iNOS and NADPH oxidase in oxidative stress and neuronal damage and the potential therapeutic strategy of the discussed compounds were represented in Figure 7. In view of the published reports and patents filed, inhibition of iNOS and NADPH oxidase by various existing and emerging molecules would be one of the ideal targets for the treatment for PD."}

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