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Ciguatera: A Treating Physician's Perspective on a Global Illness
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Ritchie C. Shoemaker, James C. Ryan
Martin further writes on investigation of the role of chronic changes in neuronal activity produced by ciguatoxin in the central nervous system. These authors showed the effect of repeated exposure over 10–13 days in vitro on gene production by PCR, specifically, upregulation of Arc and Egr1. This upregulation was prevented by prior co-incubation of the neurons with a sodium channel blocker, tetrodotoxin. Longer treatment (24 hours) of cortical neurons with ciguatoxin decreased neuronal firing and induced synaptic scaling mechanisms. Also seen was evidence of downregulation in the protein levels of glutamate receptors blocked by tetrodotoxin. The authors speculate that the neurologic symptoms of ciguatera may be explained by these compensatory mechanisms.
The Epigenetic Role of Vitamin C in Neurological Development and Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Vitamin C may also modulate the impact and regulation of other major neurotransmitters including glutamate and acetylcholine. Brain acetylcholinesterase levels were found to be decreased in guinea pigs deprived of vitamin C [48]. Rats treated with scopolamine, a drug that inhibits acetylcholinesterase activity, showed restored acetylcholine levels upon eating a vitamin C–rich diet [52]. Moreover, some evidence suggests that vitamin C can induce the release of both catecholamines and acetylcholine directly from synaptic vesicles [53]. Similarly, it has been considered a neuromodulator of glutamate dynamics and has been shown to thwart neurodegeneration following glutamate excitotoxicity in several cell and animal models [54–56]. Although the exact molecular mechanism driving this phenomenon is unclear, it is thought to be mediated by redox modulation and transcriptional regulation of neuronal glutamate receptors. Furthermore, TET-mediated DNA demethylation and methylation dynamics have been shown to regulate glutamatergic synaptic homeostasis by mediating synaptic scaling and enhancing whole-cell neuronal response to glutamate stimulation [57]. TET activity, and therefore vitamin C, are thus implicated in glutamate signaling and consequently may influence predominantly glutamatergic-driven behaviors including learning and memory. Indeed, TET1 has been previously shown to promote adult hippocampal neurogenesis and underpin learning and memory in mouse models [58]. Although the importance of TET enzymes and 5hmC is discussed later in this chapter, the role of vitamin C in neuronal function is multifaceted, as is its effect on glutamate and acetylcholine metabolism.
Perispinal etanercept advances as a neurotherapeutic
Published in Expert Review of Neurotherapeutics, 2018
Accumulating evidence, together with the fact that TNF controls both synaptic strength and synaptic scaling, supports the conclusion that one may regard excess TNF as a reversible ‘circuit breaker’ in the nervous system [2,3,6,7,20,22–27]. Etanercept’s known ability to neutralize excess TNF and reduce microglial activation, and thereby address neuroinflammation, is likely responsible for the rapid (within minutes) and prolonged neurological improvement repeatedly observed after PSE administration [2–7,9,20–27]. PSE, through its effects on neurotransmission and brain connectivity, may thus be conceptualized as flipping a switch that reactivates clinically relevant brain circuits made dormant by neuroinflammation [2–7,20–27].
Rapid improvement in severe long COVID following perispinal etanercept
Published in Current Medical Research and Opinion, 2022
Edward Tobinick, Robert N. Spengler, Tracey A. Ignatowski, Manar Wassel, Samantha Laborde
This inference is also supported by an examination of the physiologic roles of TNF in the brain. TNF is one of the small group of molecules, called gliotransmitters, that are released by glia and modulate synaptic function5,69–72. In addition to TNF, known gliotransmitters include adenosine, ATP, D-serine, GABA, and glutamate70,72. Optimal synaptic and brain neuronal network function require the presence of physiological levels of TNF69–72. The mechanisms involved in TNF modulation of neuronal, synaptic, and network function include concentration-dependent effects of TNF on astrocyte glutamate release, TNF-mediated enhancement of synaptic efficacy (synaptic strength) by increasing surface expression of AMPA receptors, TNF mediation of synaptic scaling, and TNF mediation of homeostatic synaptic plasticity69–72. The ability of excess TNF to perturb brain function is highlighted by the results of early human clinical trials of recombinant human TNF, that documented severe, but reversible, CNS adverse effects, including confusion, headache, memory loss, expressive aphasia, seizures and fatigue severe enough to preclude hospital discharge, following intravenous infusion of the cytokine73,74. One may speculate that the immediate neurological improvement documented in the present case study is due to the rapid reduction in excess TNF bioactivity produced by binding of TNF by etanercept; and that prolonged clinical improvement (here seen at 29 days after treatment) is a consequence of etanercept’s interruption of the known autocrine positive feedforward interaction that exists between TNF and microglia10,75,76.
Circulating levels of interleukin-17A, tumor necrosis factor-alpha, interleukin-18, interleukin-10, and cognitive performance of patients with relapsing-remitting multiple sclerosis
Published in Neurological Research, 2018
Anastasiya G. Trenova, Georgi S. Slavov, Milena N. Draganova-Filipova, Nonka G. Mateva, Mariya G. Manova, Lyuba D. Miteva, Spaska A. Stanilova
Keeping in mind the main limitation of the present study – measurement of cytokine concentrations in serum which are not a mirror reflection of the CSF and CNS cytokine milieu, we still believe that our results are in agreement with the hypothesis about the role of cytokine imbalance in MS-related cognitive impairment. This hypothesis is justified by the discovery of bidirectional communication between the CNS and the immune system, which is facilitated by soluble mediators, including neurotransmitters, cytokines, and hormones [38]. Both TNF-alpha and IL-17A are now regarded as one of the key players in MS pathogenesis. The expression of TNF-alpha in CNS has been shown to correlate with the course of the disease in EAE and MS [39,40]. Th-17 lymphocytes have been indicated as the ‘first wave’ passing through the blood–brain barrier in MS. Production of IL-17A by reactivated Th-17 in the CNS can stimulate astrocytes to upregulate inflammatory genes. The secretion of cytokines and chemokines from astrocytes creates an inflammatory milieu that induces damage to myelin sheaths and secondarily promotes recruitment of peripheral inflammatory cells leading to further tissue damage and lesion expansion [41]. In parallel with the structural changes in the brain, neuroinflammation may lead to cognitive and behavioral changes via multiple other mechanisms including regulation of gene expression, alterations in neuronal function, reduced neurogenesis and impaired long-term potentiation [42]. Several experimental studies have provided supportive evidence. Liu et al. [43], have demonstrated that IL-17A is a negative regulator of adult hippocampal neurogenesis in the dentate gyrus. Moreover, postoperative cognitive dysfunction in mice has been significantly associated with increased levels of IL17A and production of β-amyloid in the hippocampus [44]. A clear role for TNF-alpha has been shown in two forms of long-term plasticity in the adult brain: synaptic scaling and structural plasticity [45,46].