Terma
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connection between nitric oxide and tinnitus?
NMDA activation mechanisms directly trigger and are tightly linked to nNOS activation; in fact, some of the process is inseparable.
Separately, iNOS activation (from microglia/macrophages, including but not limited to gut issues) worsens and in a sense causes by itself NMDA-related excitotoxicity significantly: https://onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2002.00973.x
However, that last link could mislead you; nNOS importantly has a role in the cascade of NMDA activation that produces tinnitus, in a way that may make it more relevant than iNOS [and I should note, as this quote says near the end, even separately from NMDA activation!]:
Modulating Central Gain in Tinnitus: Changes in Nitric Oxide Synthase in the Ventral Cochlear Nucleus
To confirm that changes in NOS expression could be attributed to the neuronal form (nNOS), and were not due to alterations in inducible NOS (iNOS), endothelial NOS (eNOS), or an additional sub-type found in mitochondria [see Ref. (20)], we also performed immunohistochemical staining with an antibody specific to nNOS.
[...]
NO, produced post-synaptically by nNOS, acts as a retrograde neuromodulator at pre-synaptic sites to regulate plasticity in the brain and can contribute to either long-term potentiation or long-term depression, depending on local neural circuitry (53–57). A number of studies indicate that NO can also act post-synaptically to modulate long-term potentiation (58, 59). NO generation by nNOS is calcium-dependent, and is commonly associated with calcium influx via NMDA receptor-mediated ion channels. However, a study of the mouse VCN demonstrated high levels of a splice variant of nNOS that is not associated with NMDA receptors and may be associated with a different activation mechanism (60)
Beware: Contrary to popular belief, Arginine depletion is not necessarily a good thing:
Depletion of Arginine by Recombinant Arginine Deiminase Induces nNOS-Activated Neurotoxicity in Neuroblastoma Cells
Glial-derived arginine, the nitric oxide precursor, protects neurons from NMDA-induced excitotoxicity. - PubMed - NCBI
Excitotoxic neuronal cell death is characterized by an overactivation of glutamate receptors, in particular of the NMDA subtype, and the stimulation of the neuronal nitric oxide synthase (nNOS), which catalyses the formation of nitric oxide (NO) from l-arginine (L-Arg). At low L-Arg concentrations, nNOS generates NO and superoxide (O2(.)(-)), favouring the production of the toxin peroxynitrite (ONOO-). Here we report that NMDA application for five minutes in the absence of added L-Arg induces neuronal cell death, and that the presence of L-Arg during NMDA application prevents cell loss by blocking O2(.)(-) and ONOO- formation and by inhibiting mitochondrial depolarization. Because L-Arg is transferred from glial cells to neurons upon activation of glial glutamate receptors, we hypothesized that glial cells play an important modulator role in excitotoxicity by releasing L-Arg. Indeed, as we further show, glial-derived L-Arg inhibits NMDA-induced toxic radical formation, mitochondrial dysfunction and cell death. Glial cells thus may protect neurons from excitotoxicity by supplying L-Arg. This potential neuroprotective mechanism may lead to an alternative approach for the treatment of neurodegenerative diseases involving excitotoxic processes, such as ischemia.
Additionally, nNOS produces Hydrogen Peroxide in significant amounts, which becomes dominant in Arginine deficiency:
Neuronal nitric oxide synthase-derived hydrogen peroxide is a major endothelium-dependent relaxing factor. - PubMed - NCBI
The generation of free radicals by nitric oxide synthase. - PubMed - NCBI
While the generation of nitric oxide (NO*) depends solely on the binding of L-arginine, NOS produces superoxide (O(2)*(-)) and hydrogen peroxide (H(2)O(2)) when the concentration of the substrate is low.
In addition, Arginine deficiency can lead to susceptibility to [ear] infections [which associate with development of tinnitus], e.g.:
https://www.nature.com/articles/pr2...ted&code=0f24db01-60a6-4229-8a73-bb5c80f1470e
What this means is, some of the NO inhibitors (notably Arginine depletion + Lysine supplementation) promoted on this forum could potentially worsen tinnitus unexpectedly - what you would really want is a selective nNOS inhibitor, or an NOS inhibitor with only moderate effect on iNOS (and little to no effect on eNOS).