NADPH diaphorase staining neurons, uniquely resistant to toxic insults and neurodegenerative disorders, have been colocalized with neurons in the brain and peripheral tissue containing nitric oxide synthase (EC 1.14.23.-), which generates nitric oxide (NO), a recently identified neuronal messenger molecule. In the corpus striatum and cerebral cortex, NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in medium to large aspiny neurons. These same neurons colocalize with somatostatin and neuropeptide Y immunoreactivity. NO synthase immunoreactivity and NADPH diaphorase staining are colocalized in the pedunculopontine nucleus with choline acetyltransferasecontaining cells and are also colocalized in amacrine cells of the inner nuclear layer and ganglion cells of the retina, myenteric plexus neurons ofthe intestine, and ganglion cells ofthe adrenal medulla. Transfection of human kidney cells with NO synthase cDNA elicits NADPH diaphorase staining. The ratio of NO synthase to NADPH diaphorase staining in the transfected cells is the same as in neurons, indicating that NO synthase fully accounts for observed NADPH staining. The identity of neuronal NO synthase and NADPH diaphorase suggests a role for NO in modulating neurotoxicity.Nitric oxide, NO, is a prominent vascular and neuronal messenger molecule first identified as the chemical responsible for endothelium-derived relaxing factor activity (1)(2)(3). NO is also formed in macrophages and other peripheral blood cells (4, 5), though NO synthase (EC 1.14.23.-) activity of macrophages involves a distinct enzyme protein with different cofactors than the brain/endothelial enzyme (6, 7). NO synthase of brain tissue has been purified to homogeneity and shown to be a monomer of 150 kDa with an absolute requirement for calmodulin, calcium, and NADPH for enzyme activity (8). Utilizing selective antisera, we have localized the brain/endothelial enzyme by immunohistochemistry (9); besides endothelial cells, the only other localization throughout the body is in neurons and nerve processes. In the brain, NO synthase is selectively localized to discrete populations of medium-to-large aspiny neurons of the cerebral cortex and corpus striatum, basket and granule cells of the cerebellum, and other selected sites (9). In the periphery NO synthase is highly concentrated in neurons of the myenteric plexus of the small intestine, ganglion cells in the adrenal medulla, and in nerve fibers of the posterior pituitary derived from NO synthase-containing cells in the supraoptic and paraventricular hypothalamic nuclei (9).The unique pattern of NO synthase localization throughout the brain does not match precisely with any known neurotransmitters. Identifying some property that is uniquely characteristic of NO synthase-containing neurons might shed light on the biological role of NO. In the present study we show that NO synthase-containing neurons are identical with populations of neurons selectively stained for NADPH diaphorase, an oxidative enzyme localized t...

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Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19 who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic "NeuroCovid" classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the longterm sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson's disease, or Alzheimer's disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.