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SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol).

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a pandemic with the United States now carrying the highest number of cases and fatalities. Although vaccines and antiviral agents are the main focus of therapy, here we present a plausible hypothesis to leverage our understanding of neuroimmunomodulation to intervene in the pathophysiology of the disease to prevent death.

SUBMITTER: Hyoju SK

PROVIDER: S-EPMC7834242 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol).

Hyoju Sanjiv K SK Zaborina Olga O van Goor Harry H

Medical hypotheses 20200624

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now a pandemic with the United States now carrying the highest number of cases and fatalities. Although vaccines and antiviral agents are the main focus of therapy, here we present a plausible hypothesis to leverage our understanding of neuroimmunomodulation to intervene in the pathophysiology of the disease to prevent death. ...[more]

PMID: 32758881

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Project description:Severe TBI, defined as a Glasgow Coma Scale???8, increases intracranial pressure and activates the sympathetic nervous system. Sympathetic hyperactivity after TBI manifests as catecholamine excess, hypertension, abnormal heart rate variability, and agitation, and is associated with poor neuropsychological outcome. Propranolol and clonidine are centrally acting drugs that may decrease sympathetic outflow, brain edema, and agitation. However, there is no prospective randomized evidence available demonstrating the feasibility, outcome benefits, and safety for adrenergic blockade after TBI.The DASH after TBI study is an actively accruing, single-center, randomized, double-blinded, placebo-controlled, two-arm trial, where one group receives centrally acting sympatholytic drugs, propranolol (1?mg intravenously every 6?h for 7?days) and clonidine (0.1?mg per tube every 12?h for 7?days), and the other group, double placebo, within 48?h of severe TBI. The study uses a weighted adaptive minimization randomization with categories of age and Marshall head CT classification. Feasibility will be assessed by ability to provide a neuroradiology read for randomization, by treatment contamination, and by treatment compliance. The primary endpoint is reduction in plasma norepinephrine level as measured on day 8. Secondary endpoints include comprehensive plasma and urine catecholamine levels, heart rate variability, arrhythmia occurrence, infections, agitation measures using the Richmond Agitation-Sedation Scale and Agitated Behavior scale, medication use (anti-hypertensive, sedative, analgesic, and antipsychotic), coma-free days, ventilator-free days, length of stay, and mortality. Neuropsychological outcomes will be measured at hospital discharge and at 3 and 12?months. The domains tested will include global executive function, memory, processing speed, visual-spatial, and behavior. Other assessments include the Extended Glasgow Outcome Scale and Quality of Life after Brain Injury scale. Safety parameters evaluated will include cardiac complications.The DASH After TBI Study is the first randomized, double-blinded, placebo-controlled trial powered to determine feasibility and investigate safety and outcomes associated with adrenergic blockade in patients with severe TBI. If the study results in positive trends, this could provide pilot evidence for a larger multicenter randomized clinical trial. If there is no effect of therapy, this trial would still provide a robust prospective description of sympathetic hyperactivity after TBI.ClinicalTrials.gov NCT01322048.

Project description:1. The aim of the present study was to compare the effects of the centrally acting antihypertensive drugs rilmenidine, moxonidine, clonidine and guanabenz on sympathetic tone with their effects on noradrenaline release in the cerebral cortex. In particular, the hypothesis was tested that rilmenidine and moxonidine, due to their high affinity for sympatho-inhibitory imidazoline I(1) receptors and low affinity for alpha(2)-adrenoceptors, lower sympathetic tone without causing an alpha(2)-adrenoceptor-mediated inhibition of cerebrocortical noradrenaline release. 2. In rats anaesthetized with urethane, blood pressure and heart rate were measured and the concentration of noradrenaline in arterial blood plasma was determined. The release of noradrenaline in the medial prefrontal cortex was estimated by microdialysis. Intravenous administration of rilmenidine (30, 100, 300 and 1000 microg kg(-1)), moxonidine (10, 30, 100 and 300 microg kg(-1)), clonidine (1, 3, 10 and 30 microg kg(-1)) and guanabenz (1, 3, 10 and 30 microg kg(-1)) led to dose-dependent hypotension and bradycardia; the plasma noradrenaline concentration also decreased. After the two highest doses, all four drugs lowered noradrenaline release in the prefrontal cortex. At doses eliciting equal hypotensive and sympatho-inhibitory responses, rilmenidine and moxonidine inhibited cerebral cortical noradrenaline release at least as much as clonidine and guanabenz. 3. The results show that rilmenidine and moxonidine lower cerebrocortical noradrenaline release at doses similar to those which cause sympatho-inhibition. This effect was probably due to an alpha(2)-adrenoceptor-mediated inhibition of the firing of locus coeruleus neurons and, in addition, to presynaptic inhibition of noradrenaline release at the level of the axon terminals in the cortex. The results argue against the hypothesis that rilmenidine and moxonidine, due to their selectivity for sympatho-inhibitory I(1) imidazoline receptors, do not suppress noradrenergic neurons in the central nervous system.

Dataset Information

SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol).

Publications

SARS-CoV-2 and the sympathetic immune response: Dampening inflammation with antihypertensive drugs (Clonidine and Propranolol).

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