Noradrenaline transmission reducing drugs may protect against a broad range of diseases.

Fitzgerald, Paul J.

doi:10.1111/aap.12019

Cited by 15 publications

(10 citation statements)

References 116 publications

(125 reference statements)

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“…Of interest, elevated NAD transmission has been associated with some cases of epilepsy (Fitzgerald, 2010) and although some studies show contradictory results (Svob Strac et al, 2016), also evidence exists supporting the use of NAD-decreasing drugs in the treatment of neurological diseases, including epilepsy (Fitzgerald, 2015). …”

Section: Discussionmentioning

confidence: 99%

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Smolders²,

et al. 2017

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Dravet syndrome (DS) is a genetic encephalopathy that is characterized by severe seizures and prominent co-morbidities (e.g., physical, intellectual disabilities). More than 85% of the DS patients carry an SCN1A mutation (sodium channel, voltage gated, type I alpha subunit). Although numerous anti-epileptic drugs have entered the market since 1990, these drugs often fail to adequately control seizures in DS patients. Nonetheless, current clinical data shows significant seizure reduction in DS patients treated with the serotonergic (5-hydroxytryptamine, 5-HT) drug fenfluramine (FA). Recent preclinical research confirmed the anti-epileptiform activity of FA in homozygous scn1a mutant zebrafish larvae that mimic DS well. Here we explored the anti-epileptiform mechanisms of FA by investigating whether selective agonists/antagonists of specific receptor subtypes were able to counteract the FA-induced inhibition of seizures and abnormal brain discharges observed in the scn1a mutants. We show that antagonists of 5-HT1D and 5-HT2C receptor subtypes were able to do so (LY 310762 and SB 242084, respectively), but notably, a 5-HT2A-antagonist (ketanserin) was not. In addition, exploring further the mechanism of action of FA beyond its serotonergic profile, we found that the anti-epileptiform brain activity of FA was significantly abolished when it was administered in combination with a σ1-agonist (PRE 084). Our study therefore provides the first evidence of an involvement of the σ1 receptor in the mechanism of FA. We further show that the level of some neurotransmitters [i.e., dopamine and noradrenaline (NAD)] in head homogenates was altered after FA treatment, whereas γ-aminobutyric acid (GABA) and glutamate levels were not. Of interest, NAD-decreasing drugs have been employed successfully in the treatment of neurological diseases; including epilepsy and this effect could contribute to the therapeutic effect of the compound. In summary, we hypothesize that the anti-epileptiform activity of FA not only originates from its 5-HT1D- and 5-HT2C-agonism, but likely also from its ability to block σ1 receptors. These findings will help in better understanding the pharmacological profile of compounds that is critical for their applicability in the treatment of DS and possibly also other drug-resistant epilepsies.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Smolders²,

et al. 2017

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“…Surprisingly no studies have been published on the effect of alpha-1 adrenergic blocker antihypertensives in mania but there are several studies with them in the treatment of PTSD [97]. …”

Section: Similarities and Differences Between Essential Hypertensimentioning

confidence: 99%

Is Mania the Hypertension of the Mood? Discussion of A Hypothesis

Rihmer

Gonda²,

Döme³

2017

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Beyond both being biphasic/bidirectional disorders (hypo)mania and essential hypertension share a surprising number of similarities and an overlap between their genetics, biological background, underlying personality and temperamental factors, precipitating factors, comorbidity and response to treatment, indicating a possibly partially shared biological background. Based on theoretical knowledge, similarities related to characteristics, manifestation and course, and the results of pharmacological studies related to the effects and side effects of pharmacotherapies used in the treatment of these two distinct disorders, the authors outline a hypothesis discussing the similar origins of these two phenomena and thus mania being the hypertension of mood in memory of Athanasios Koukopoulos, one of the greatest researchers and theoreticists of mania of all time.

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“…Furthermore, as human studies directly linking stress and (auto)immune response are lacking, owing to practical and ethical concerns (139), EAE models, despite limitations (5), should be considered for investigating role of stress in triggering MS, and particularly pharmacological treatments affecting catecholamine action trough distinct types of adrenoceptors. Considering that individual's elevated noradrenergic tone (e.g., due to genetics) may favor MS onset (140), such investigation should encompass animals of different genetic makeup.…”

Section: Putative Research Directionsmentioning

confidence: 99%

Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

et al. 2020

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The role of stress effector systems in the initiation and progression of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), the most commonly used experimental model of MS, has strongly been suggested. To corroborate this notion, alterations in activity of the sympathoadrenal and sympathoneural axes of sympathoadrenal system (a major communication pathway between the central nervous system and the immune system), mirrored in altered release of their end-point mediators (adrenaline and noradrenaline, respectively), are shown to precede (in MS) and/or occur during development of MS and EAE in response to immune cell activation (in early phase of disease) and disease-related damage of sympathoadrenal system neurons and their projections (in late phase of disease). To add to the complexity, innate immunity cells and T-lymphocytes synthesize noradrenaline that may be implicated in a local autocrine/paracrine self-amplifying feed-forward loop to enhance myeloid-cell synthesis of proinflammatory cytokines and inflammatory injury. Furthermore, experimental manipulations targeting noradrenaline/adrenaline action are shown to influence clinical outcome of EAE, in a disease phase-specific manner. This is partly related to the fact that virtually all types of cells involved in the instigation and progression of autoimmune inflammation and target tissue damage in EAE/MS express functional adrenoceptors. Although catecholamines exert majority of immunomodulatory effects through β 2-adrenoceptor, a role for α-adrenoceptors in EAE pathogenesis has also been indicated. In this review, we summarize all aforementioned aspects of immunopathogenetic action of catecholamines in EAE/MS as possibly important for designing new strategies targeting their action to prevent/mitigate autoimmune neuroinflammation and tissue damage.

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Noradrenaline transmission reducing drugs may protect against a broad range of diseases.

Cited by 15 publications

References 116 publications

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Pharmacological Analysis of the Anti-epileptic Mechanisms of Fenfluramine in scn1a Mutant Zebrafish

Is Mania the Hypertension of the Mood? Discussion of A Hypothesis

Role of the End-Point Mediators of Sympathoadrenal and Sympathoneural Stress Axes in the Pathogenesis of Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis

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