Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy

Abstract

Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6–9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available. Consequently, distinct pharmacological targets have been explored and investigated in clinical studies based on MSA-related symptoms and pathomechanisms. Parkinsonism, cerebellar ataxia, and autonomic failure are the most important symptoms targeted by symptomatic treatments in current clinical trials. The most prominent pathological hallmark is oligodendroglial cytoplasmic inclusions containing alpha-synuclein, thus classifying MSA as synucleinopathy. Additionally, myelin and neuronal loss accompanied by micro- and astrogliosis are further distinctive features of MSA-related neuropathology present in numerous brain regions. Besides summarizing current symptomatic treatment strategies in MSA, this review critically reflects upon potential cellular targets and disease-modifying approaches for MSA such as (I) targeting α-syn pathology, (II) intervening neuroinflammation, and (III) neuronal loss. Although these single compound trials are aiming to interfere with distinct pathogenetic steps in MSA, a combined approach may be necessary to slow down the rapid progression of the oligodendroglial associated synucleinopathy.

Activity-Based Hydrazine Probes for Protein Profiling of Electrophilic Functionality in Therapeutic Targets

“…Indeed, phenelzine is known to have antiaddictive effects, 50 , 51 and MAOIs have reported efficacy for fibromyalgia, 52 pain, 53 bipolar disorder, 54 Parkinson’s disease, 55 and multiple-system atrophy. 56 Taken together, these facts indicate that MAOIs and their targets have druggable potential for a broad spectrum of brain diseases. Guided by the principles of ABPP, organohydrazines may serve as a broadly useful pharmacophore to explore target–phenotype relationships.…”

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

“…Symptomatic treatments are available, although MSA patients usually show poor l-Dopa responsiveness [100]. Concerning possible disease-modifying therapies, the following strategies are under clinical trials: targeting SYN pathology such as active and passive immunization, anti-aggregative small molecules, RNA interference techniques and an increase in SYN clearance, intervening neuroinflammation or neuronal loss (by stem cells) [25,92,[100][101][102]. Remyelinating molecules are also being tested in clinical trials in the case of MSA, since this disease is accompanied by myelin loss as well [100].…”

MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases

“…Multiple system atrophy (MSA) is a devastating neurodegenerative disease representing parkinsonism, cerebellar ataxia, autonomic dysfunction, and pyramidal signs [197]. MSA, clinically predominated by parkinsonism, is defined as MSA-P, while that predominated by cerebellar ataxia is called MSA-C. MSA patients show significant brain atrophy of the putamen, cerebellum, pons, or middle cerebellar peduncle with mild cortical atrophy in the frontal lobes.…”