Neurotoxicity nitric oxide synthase

Itzhak, Y., Gandia, C., Huang, P.L., Ali, S.F. Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity. J. Pharmacol. Exp. Ther. 284 1040, 1998. 

M. F., Inhibition of neuronal nitric oxide synthase by 7-nitroindazole protects against MPTP-induced neurotoxicity in mice, J. Neurochem. 

Dawson, V.L., Kizushi, V.M., Huang, P.L., Snyder S.H., Dawson, T.M. Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice, J. Neurosci 1996, 16, 2479-2487. 

Nitric Oxide Synthase in Neurotoxicity Mediated by Glutamate... 

Fig. 8.1 A schematic diagram illustrating the involvement of NF-k I in gpl20, ROS, NO, PG, IL-1/3 and TNF-a-mediated neurotoxicity. NMDA-R, N-Methyl-D-aspartate receptor, cPLA2, cytosolic phospholipase A2 lyso-PtdCho, lysophosphatidylcholine AA, arachidonic acid cAMP, cyclic adenosine monophosphate PKA, protein kinase A TNF-a, tumor necrosis factor-a TNF-a-R, TNF-a-receptor IL-1/8, interleukin-1 /3 IL-l/i-R, IL-1/8-receptor, IL-6, interleukin-6 MARK, mitogen-activated protein kinase NO, nitric oxide PG, prostaglandins EP-R, prostaglandin receptors NF-kB, nuclear factor-icB NF-kB-RE, nuclear factor-/cB-response element I/cB, inhibitory subunit of NF-icB HIV-1, human immunodeficiency virus type 1 gpl20, HIV-1 coat glycoprotein COX-2, cyclooxygenase-2 iNOS, inducible nitric oxide synthase SPLA2, secretory phospholipase A2 SOD, superoxide dismutase MMP, matrix metalloproteinase and VCAM-1, vascular adhesion molecule-1...

DOM treatment also rapidly decreases cellular GSH, which precedes neurotoxicity. This decrease is primarily due to DOM-mediated GSH efflux. DOM also induces an increase in oxidative stress as indicated by increases in ROS and lipid peroxidation products, which follow GSH efflux. Astrocytes from both genotypes are resistant to DOM-mediated neurotoxicity and present a diminished Ca2+ response to DOM-mediated toxicity (Walser et al., 2006). Exposure of neonatal rat microglia to DOM triggers the release of TNF-a and matrix metalloproteinase-9 (MMP-9) (Mayer et al., 2001). These molecules are involved in the modulation of neuroinflammation in brain (Farooqui et al., 2007). Collective evidence suggests that DOM-mediated neurodegeneration involves changes in cellular redox, oxidative stress, and increased expression of cytokines, nitric oxide synthase, NADPH diaphorase, and matrix metalloproteinase-9 (Walser et al., 2006 Chandrasekaran et al., 2004 Ananth et al., 2003a,b Mayer et al., 2001). 

Ananth C., Gopalakrishnakone P., and Kaur C. (2003b). Induction of inducible nitric oxide synthase expression in activated microglia following domoic acid (DA)-induced neurotoxicity in the rat hippocampus. Neurosci. Lett. 338 49-52. 

Itzhak Y, Ali SF (1996) The neuronal nitric oxide synthase inhibitor, 7-nitroindazole, protects against methamphetamine-induced neurotoxicity in vivo. J. Neurochem., 67 1770-1773. 

Dawson TM, Steiner JP, Dawson VL, Dinerman JL, Uhl GR, Snyder SFI. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci U S A 1993 90 9808-9812. 

Dawson, V., Brahmbhatt, H. P., Mong, J. A., and Dawson, T. M. (1994). Expression of inducible nitric oxide synthase causes delayed neurotoxicity in primary mixed neuronal-glial cortical cultures. Neuropharmacology 33, 1425-1430. 

Watanabe H, Muramatsu Y, Kurosaki R et al. Proteotive effects of neuronal nitric oxide synthase inhibitor in mouse brain against MPTP neurotoxicity an immunohistological study. Eur Neuropsychopharmacol 2004 14 93-104. 

Evidence indicates exposure to nanoparticles can induce an inflammatory response in the CNS. For example, when a sample of mice were exposed to airborne particle matter, increased levels of pro-inflammatory cytokines (TNF-a IL-la), transcription factor, and nuclear factor-kappa beta (NF-k/3) were observed (114). TNF-a serves a neuroprotective function (115), but given certain pathogens TNF-a can be neurotoxic (116-120). IL-a activates cyclooxygenase (COX)-2, phospholipase A2, and inducible nitric oxide synthase (iNOS) activity, which are all associated with inflammation and immune response (121). IL-a is also partially responsible for increasing the permeability of the blood-brain barrier (122, 123). Thus, there is great interest in better understanding how nanoparticles enter the body and translocate as this will impact all organs and thus the toxicity of nanomaterials. 

In addition to nitric oxide, superoxide, and peroxynitrite, NO synthases are able to generate secondary free radicals because similar to cytochrome P-450 reductase, the reductase domain can transfer an electron from the heme to a xenobiotic. Thus it has been found [158,159] that neuronal NO synthase NOS I catalyzed the formation of CH3CH(OH) radical from ethanol. It was suggested that the perferryl complex of NOS I is responsible for the formation of such secondary radicals. Miller [160] also demonstrated that 1,3-dinitrobenzene mediated the formation of superoxide by nNOS. It was proposed that the enhancement of superoxide production in the presence of 1,3-dinitrobenzene converted nNOS into peroxynitrite-produced synthase and may be a mechanism of neurotoxicity of certain nitro compounds. 

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