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Medicine Feb 2024Multiple sclerosis (MS) is a chronic autoimmune disease with demyelination, inflammation, neuronal loss, and gliosis (scarring). Our object to review MS pathophysiology... (Review)
Review
Multiple sclerosis (MS) is a chronic autoimmune disease with demyelination, inflammation, neuronal loss, and gliosis (scarring). Our object to review MS pathophysiology causes and treatment. A Narrative Review article was conducted by searching on Google scholar, PubMed, Research Gate about relevant keywords we exclude any unique cases and case reports. The destruction of myelinated axons in the central nervous system reserves this brunt. This destruction is generated by immunogenic T cells that produce cytokines, copying a proinflammatory T helper cells1-mediated response. Autoreactive cluster of differentiation 4 + cells, particularly the T helper cells1 subtype, are activated outside the system after viral infections. T-helper cells (cluster of differentiation 4+) are the leading initiators of MS myelin destruction. The treatment plan for individuals with MS includes managing acute episodes, using disease-modifying agents to decrease MS biological function of MS, and providing symptom relief. Management of spasticity requires physiotherapy, prescription of initial drugs such as baclofen or gabapentin, secondary drug options such as tizanidine or dantrolene, and third-line treatment such as benzodiazepines. To treat urinary incontinence some options include anticholinergic medications such as oxybutynin hydrochloride, tricyclic antidepressants (such as amitriptyline), and intermittent self-catheterization. When it comes to bowel problems, one can try to implement stool softeners and consume a high roughage diet. The review takes about MS causes Pathophysiology and examines current treatment strategies, emphasizing the advancements in disease-modifying therapies and symptomatic treatments. This comprehensive analysis enhances the understanding of MS and underscores the ongoing need for research to develop more effective treatments.
Topics: Humans; Multiple Sclerosis; Treatment Outcome; Chronic Disease; Muscle Spasticity
PubMed: 38394496
DOI: 10.1097/MD.0000000000037297 -
Neuromuscular Disorders : NMD Oct 2023Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in...
Mutations in RYR1 encoding the ryanodine receptor (RyR) skeletal muscle isoform (RyR1) are a common cause of inherited neuromuscular disorders. Despite its expression in a wide range of tissues, non-skeletal muscle manifestations associated with RYR1 mutations have only been rarely reported. Here, we report three patients with a diagnosis of Central Core Disease (CCD), King-Denborough Syndrome (KDS) and Malignant Hyperthermia Susceptibility (MHS), respectively, who in addition to their (putative) RYR1-related disorder also developed symptoms and signs of acute pancreatitis. In two patients, episodes were recurrent, with severe multisystem involvement and sequelae. RyR1-mediated calcium signalling plays an important role in normal pancreatic function but has also been critically implicated in the pathophysiology of acute pancreatitis, particularly in bile acid- and ethanol-induced forms. Findings from relevant animal models indicate that pancreatic damage in these conditions may be ameliorated through administration of the specific RyR1 antagonist dantrolene and other compounds modifying pancreatic metabolism including calcium signalling. These observations suggest that patients with RYR1 gain-of-function variants may be at increased risk of developing acute pancreatitis, a condition which should therefore be considered in the health surveillance of such individuals.
Topics: Animals; Humans; Acute Disease; Calcium; Malignant Hyperthermia; Mutation; Pancreatitis; Ryanodine Receptor Calcium Release Channel
PubMed: 37783627
DOI: 10.1016/j.nmd.2023.09.003 -
American Journal of Physiology. Heart... Oct 2023Ryanodine receptor 2 (RyR2) hyperactivity is observed in structural heart diseases that are a result of ischemia or heart failure. It causes abnormal calcium handling...
Ryanodine receptor 2 (RyR2) hyperactivity is observed in structural heart diseases that are a result of ischemia or heart failure. It causes abnormal calcium handling and calcium leaks that cause metabolic, electrical, and mechanical dysfunction, which can trigger arrhythmias. Here, we tested the antiarrhythmic potential of dantrolene (RyR inhibitor) in human hearts. Human hearts not used in transplantation were obtained, and right ventricular outflow tract (RVOT) wedges and left ventricular (LV) slices were prepared. Pseudo-ECGs were recorded to determine premature ventricular contraction (PVC) incidences. Optical mapping was performed to determine arrhythmogenic substrates. After baseline optical recordings, tissues were treated with ) isoproterenol (250 nM), ) caffeine (200 mM), and ) dantrolene (2 or 10 mM). Optical recordings were obtained after each treatment. Isoproterenol and caffeine treatment increased PVC incidence, whereas dantrolene reduced the PVC burden. Isoproterenol shortened action potential duration (APD) in the RV, RVOT, and LV regions and shortened calcium transient duration (CaTD) in the LV. Caffeine further shortened APD in the RV, did not modulate APD in the RVOT, and prolonged APD in the LV. In addition, in the LV, CaTD prolongation was also observed. More importantly, adding dantrolene did not alter APD in the RV or RVOT regions but produced a trend toward APD prolongation and significant CaTD prolongation in the LV, restoring these parameters to baseline values. In conclusions, dantrolene treatment suppresses triggers and reverses arrhythmogenic substrates in the human heart and could be a novel antiarrhythmic therapy in patients with structural heart disease. Ryanodine receptor 2 hyperactivity is observed in structural heart diseases caused by ischemia or heart failure. It causes abnormal calcium leaks, which can trigger arrhythmias. To prevent arrhythmias, we applied dantrolene in human hearts ex vivo. Isoproterenol and caffeine treatment increased PVC incidence, whereas dantrolene reduced the PVC burden. Dantrolene treatment suppresses triggers and reverses arrhythmogenic substrates and could be a novel antiarrhythmic therapy in patients with structural heart disease.
Topics: Humans; Ryanodine Receptor Calcium Release Channel; Dantrolene; Isoproterenol; Ryanodine; Calcium; Caffeine; Arrhythmias, Cardiac; Anti-Arrhythmia Agents; Heart Failure; Action Potentials
PubMed: 37566110
DOI: 10.1152/ajpheart.00103.2023 -
CNS Drugs Mar 2024Multiple sclerosis is a chronic inflammatory disease that affects the central nervous system and can cause various types of pain including ongoing extremity pain,... (Review)
Review
Multiple sclerosis is a chronic inflammatory disease that affects the central nervous system and can cause various types of pain including ongoing extremity pain, Lhermitte's phenomenon, trigeminal neuralgia, and mixed pain. Neuropathic pain is a major concern for individuals with multiple sclerosis as it is directly linked to myelin damage in the central nervous system and the management of neuropathic pain in multiple sclerosis is challenging as the options available have limited efficacy and can cause unpleasant side effects. The literature search was conducted across two databases, PubMed, and Google Scholar. Eligible studies included clinical trials, observational studies, meta-analyses, systematic reviews, and narrative reviews. The objective of this article is to provide an overview of literature on pharmacological and non-pharmacological strategies employed in the management of neuropathic pain in multiple sclerosis. Pharmacological options include cannabinoids, muscle relaxants (tizanidine, baclofen, dantrolene), anticonvulsants (benzodiazepines, gabapentin, phenytoin, carbamazepine, lamotrigine), antidepressants (duloxetine, venlafaxine, tricyclic antidepressants), opioids (naltrexone), and botulinum toxin variants, which have evidence from various clinical trials. Non-pharmacological approaches for trigeminal neuralgia may include neurosurgical methods. Non-invasive methods, physical therapy, and psychotherapy (cognitive behavioral therapy, acceptance and commitment therapy and mindfulness-based stress reduction) may be recommended for patients with neuropathic pain in multiple sclerosis. The choice of treatment depends on the severity and type of pain as well as other factors, such as patient preferences and comorbidities. There is a pressing need for healthcare professionals and researchers to prioritize the development of better strategies for managing multiple sclerosis-induced neuropathic pain.
Topics: Humans; Multiple Sclerosis; Trigeminal Neuralgia; Acceptance and Commitment Therapy; Neuralgia; Antidepressive Agents; Anticonvulsants
PubMed: 38421578
DOI: 10.1007/s40263-024-01072-5 -
Scientific Reports Sep 2023Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum....
Physiological muscle contraction requires an intact ligand gating mechanism of the ryanodine receptor 1 (RyR1), the Ca-release channel of the sarcoplasmic reticulum. Some mutations impair the gating and thus cause muscle disease. The RyR1 mutation T4706M is linked to a myopathy characterized by muscle weakness. Although, low expression of the T4706M RyR1 protein can explain in part the symptoms, little is known about the function RyR1 channels with this mutation. In order to learn whether this mutation alters channel function in a manner that can account for the observed symptoms, we examined RyR1 channels isolated from mice homozygous for the T4709M (TM) mutation at the single channel level. Ligands, including Ca, ATP, Mg and the RyR inhibitor dantrolene were tested. The full conductance of the TM channel was the same as that of wild type (wt) channels and a population of partial open (subconductive) states were not observed. However, two unique sub-populations of TM RyRs were identified. One half of the TM channels exhibited high open probability at low (100 nM) and high (50 μM) cytoplasmic [Ca], resulting in Ca-insensitive, constitutively high P channels. The rest of the TM channels exhibited significantly lower activity within the physiologically relevant range of cytoplasmic [Ca], compared to wt. TM channels retained normal Mg block, modulation by ATP, and inhibition by dantrolene. Together, these results suggest that the TM mutation results in a combination of primary and secondary RyR1 dysfunctions that contribute to disease pathogenesis.
Topics: Animals; Mice; Ryanodine Receptor Calcium Release Channel; Dantrolene; Muscular Diseases; Cytoplasm; Myotonia Congenita; Adenosine Triphosphate
PubMed: 37670077
DOI: 10.1038/s41598-023-41801-2 -
Heart Rhythm O2 Sep 2023Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase...
BACKGROUND
Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase cardiac arrhythmia risk. However, it is unknown whether alcohol and caffeine co-consumption can synergistically enhance cardiac arrhythmogenesis.
OBJECTIVE
The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis.
METHODS
A binge drinking rat model (alcohol 2 g/kg, intraperitoneal, every other day for 3 times) was used. Rats (4 months old, both sexes) were randomized into the following 4 groups: binge alcohol-only group (A) (n = 8), nonalcohol, caffeine-only (60 mg/kg, intraperitoneal) group (C) (n = 8), binge alcohol plus caffeine group (A+C) (n = 8), and binge alcohol + caffeine + dantrolene group (A+D) (n = 7, treated with dantrolene 10 mg/kg before each alcohol injection). We also investigated whether alcohol induces Ca sparks and dantrolene treatment attenuates alcohol-induced Ca leak in ventricular myocytes.
RESULTS
No arrhythmia was induced with caffeine alone (group C, n = 0 of 8) or alcohol alone (group A, n = 0 of 8). However, alcohol + caffeine induced spontaneous ventricular tachyarrhythmias in all rats (group A+C, n = 8 of 8; < .001 vs group C or A). Dantrolene prevented ventricular tachyarrhythmia induction in all 7 rats (group A+D, n = 0 of 7; < .001 vs group A+C). In isolated ventricular myocytes, alcohol significantly increased Ca sparks and dantrolene treatment reduced alcohol-induced Ca sparks.
CONCLUSION
Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca sparks in vitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias in vivo.
PubMed: 37744935
DOI: 10.1016/j.hroo.2023.07.005 -
Journal of Molecular and Cellular... Aug 2023Diastolic Ca leak due to cardiac ryanodine receptor (RyR2) hyperactivity has been widely documented in chronic ischemic heart disease (CIHD) and may contribute to...
Diastolic Ca leak due to cardiac ryanodine receptor (RyR2) hyperactivity has been widely documented in chronic ischemic heart disease (CIHD) and may contribute to ventricular tachycardia (VT) risk and progressive left-ventricular (LV) remodeling. Here we test the hypothesis that targeting RyR2 hyperactivity can suppress VT inducibility and progressive heart failure in CIHD by the RyR2 inhibitor dantrolene. METHODS AND RESULTS: CIHD was induced in C57BL/6 J mice by left coronary artery ligation. Four weeks later, mice were randomized to either acute or chronic (6 weeks via implanted osmotic pump) treatment with dantrolene or vehicle. VT inducibility was assessed by programmed stimulation in vivo and in isolated hearts. Electrical substrate remodeling was assessed by optical mapping. Ca sparks and spontaneous Ca releases were measured in isolated cardiomyocytes. Cardiac remodeling was quantified by histology and qRT-PCR. Cardiac function and contractility were measured using echocardiography. Compared to vehicle, acute dantrolene treatment reduced VT inducibility. Optical mapping demonstrated reentrant VT prevention by dantrolene, which normalized the shortened refractory period (VERP) and prolonged action potential duration (APD), preventing APD alternans. In single CIHD cardiomyocytes, dantrolene normalized RyR2 hyperactivity and prevented spontaneous intracellular Ca release. Chronic dantrolene treatment not only reduced VT inducibility but also reduced peri-infarct fibrosis and prevented further progression of LV dysfunction in CIHD mice. CONCLUSIONS: RyR2 hyperactivity plays a mechanistic role for VT risk, post-infarct remodeling, and contractile dysfunction in CIHD mice. Our data provide proof of concept for the anti-arrhythmic and anti-remodeling efficacy of dantrolene in CIHD.
Topics: Animals; Mice; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Dantrolene; Mice, Inbred C57BL; Myocardial Ischemia; Myocytes, Cardiac; Ryanodine; Ryanodine Receptor Calcium Release Channel; Tachycardia, Ventricular
PubMed: 37285929
DOI: 10.1016/j.yjmcc.2023.05.009 -
Life Science Alliance Feb 2024In the heart, genetic or acquired mishandling of diastolic [Ca] by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac...
In the heart, genetic or acquired mishandling of diastolic [Ca] by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac death. Strategies to avoid these risks include decrease of Ca release by drugs modulating RyR2 activity or increase in Ca uptake by drugs modulating SR Ca ATPase (SERCA2a) activity. Here, we combine these strategies by developing experimental compounds that act simultaneously on both processes. Our screening efforts identified the new 1,4-benzothiazepine derivative GM1869 as a promising compound. Consequently, we comparatively studied the effects of the known RyR2 modulators Dantrolene and S36 together with GM1869 on RyR2 and SERCA2a activity in cardiomyocytes from wild type and arrhythmia-susceptible RyR2 mice by confocal live-cell imaging. All drugs reduced RyR2-mediated Ca spark frequency but only GM1869 accelerated SERCA2a-mediated decay of Ca transients in murine and human cardiomyocytes. Our data indicate that S36 and GM1869 are more suitable than dantrolene to directly modulate RyR2 activity, especially in RyR2 mice. Remarkably, GM1869 may represent a new dual-acting lead compound for maintenance of diastolic [Ca].
Topics: Animals; Humans; Mice; Arrhythmias, Cardiac; Biological Transport; Dantrolene; Myocytes, Cardiac; Ryanodine Receptor Calcium Release Channel
PubMed: 38012000
DOI: 10.26508/lsa.202302278