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Mesolimbic Interactions with Mesopontine Modulation of Locomotion
Published in Peter W. Kalivas, Charles D. Barnes, Limbic Motor Circuits and Neuropsychiatry, 2019
Robert D. Skinner, E. Garcia-Rill
Another role of NO in the nervous system appears to be that of a neurotoxin. Because NO has free radical chemical properties, it is highly reactive and, thus, toxic. In primary cerebral cortical cultures, NMDA added to the culture medium induced the release of NO from NOS-containing neurons. Neurons adjacent to the extensively branched NOS-containing neurons were killed while NOS-containing neurons survived. This neurotoxicity was prevented by addition of N-nitroarginine or N-methylarginine, two antagonists of arginine, or hemoglobin, which binds extracellular NO.196 The clinical import of NO was heralded recently in a study of experimental stroke in an in vivo rat model in which N-nitroarginine was shown to provide better protection against ischemic-induced damage than the NMDA antagonist MK-801.203 It appears that NOS-containing neurons may have a role in Huntington’s disease in which massive loss of caudate nucleus neurons occurs, but NOS-containing neurons are resistive to the destructive process.204 It even seems possible that in patients with elevated numbers of cholinergic PPN cells (NOS-containing), the onset of puberty, with its increased levels of sex steroids, may bring about increased activity of PPN cells. The consequence of this increased neuronal activity may be, (a) toxic levels of NO are produced due to the additional PPN NOS-containing cells, (b) death of non-NOS-containing neurons in close association with PPN neurons, and (c) the subsequent onset of the symptoms of schizophrenia or narcolepsy at age 20 ± 6 years.
Analgesic and anti-inflammatory effects of modafinil in a mouse model of neuropathic pain: A role for nitrergic and serotonergic pathways
Published in Neurological Research, 2022
Hossein Ghorbanzadeh, Parastoo Mohebkhodaei, Mehran Nematizadeh, Nastaran Rahimi, Mahsa Rafeiean, Mehdi Ghasemi, Ahmad R. Dehpour
Modafinil, 7-nitroindazole (7-NI; a selective nNOS inhibitor), citalopram (a selective serotonin reuptake inhibitor; SSRI), aminoguanidine (a selective inducible NOS inhibitor), and L-NG-nitroarginine methyl ester (L-NAME; a nonspecific NOS inhibitor) were purchased from Sigma-Aldrich (Germany). Xylazine and ketamine were purchased from Alfasanco (Woerden, Holland) and dimethylsulfoxide (DMSO), Tween 80, and formalin solution were bought from Merck Company (UK). Modafinil suspension was made using tween 80 1%. 7-NI was dissolved in DMSO 10%. Other chemicals were dissolved in saline. All drugs were prepared freshly before the experiments and injected intraperitoneally (i.p.) in a volume of 10 ml/kg. Mouse-specific enzyme-linked immunosorbent assay (ELISA) kits for measuring IL-6 and TNF- α were bought from DuoSet (R&D systems, United States). Nitric Oxide assay kit was bought from ZellBio GmbH (Germany).
Lamotrigine as a mood stabilizer: insights from the pre-clinical evidence
Published in Expert Opinion on Drug Discovery, 2019
Aline Silva de Miranda, Amanda Silva de Miranda, Antônio Lúcio Teixeira
Nitric oxide (NO) synthesis from its precursor L-arginine by nitric oxide synthase (NOS) is dependent on the activation of NMDA receptors [90,91]. Therefore, it is reasonable to hypothesize that antidepressant properties of LTG might also be mediated by NO-dependent mechanisms. Antidepressant-like effects of NOS inhibitors have been demonstrated in previous studies [92–94]. Sub-effective dose of L-arginine (750 mg/kg, i.p., a substrate for NOS) injected in mice 30 min before the effective dose of LTG (10 mg/kg, i.p.) reversed its antidepressant-like effect in the FST. When sub-effective dose of LTG (5 mg/kg, i.p.) was co-administered with sub-effective doses of L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p., a non-specific NOS inhibitor) or 7-nitroindazole (7-NI, 30 mg/kg, a neuronal NOS inhibitor), there was decrease in the immobility time in the FST. Taken together, these findings support a role for NO in LTG-associated antidepressant actions [86].
Equilibria, kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine
Published in Drug Development and Industrial Pharmacy, 2018
Pham Van Quyet, Bernice Mei Jin Tan, Celine Valeria Liew, Lai Wah Chan, Quan Sing Ng, Paul Wan Sia Heng
The controlled decrease in tumor blood flow to cause cancer cell death has been exploited as a means for enhancing cancer treatments [1]. Nitric oxide, a vasodilation mediator, is normally produced from L-arginine and L-citrulline by the action of nitric oxide synthase in the body. The competitive inhibition of nitric oxide synthase by L-arginine analogs, such as L-NG-nitroarginine (LNNA), L-NG-nitroarginine methyl ester, and L-NG-monomethyl arginine acetate has been reported to modify the blood flow of murine tissues in several preclinical studies [2–4]. A dose of 1 mg/kg of LNNA administered via the intravenous route to rats resulted in the selective reduction of tumor blood flow compared to normal tissues. Despite its potential application as an adjuvant to existing cancer therapies, there are no studies to date which explore the development of LNNA into an injectable formulation suitable for human administration. This is believed to be partly related to its poor aqueous solubility and lack of information regarding its chemical properties, stability, and pharmacokinetic profile.