Nicotinic α7 receptor-induced adenosine release from perisynaptic Schwann cells controls acetylcholine spillover from motor endplates.

Acetylcholine (ACh) spillover from motor endplates occurs after neuronal firing bursts being potentiated by cholinesterase inhibitors (e.g., neostigmine). Nicotinic α7 receptors (α7nAChR) on perisynaptic Schwann cells (PSCs) can control ACh spillover by unknown mechanisms. We hypothesized that adenosine might be the gliotransmitter underlying PSCs-nerve terminal communication. Rat isolated hemidiaphragm preparations were used to measure (1) the outflow of [3 H]ACh, (2) real-time transmitter exocytosis by video-microscopy with the FM4-64 fluorescent dye, and (3) skeletal muscle contractions during high-frequency (50 Hz) nerve stimulation bursts in the presence of a selective α7nAChR agonist, PNU 282987, or upon inhibition of cholinesterase activity with neostigmine. To confirm our prediction that α7nAChR-mediated effects require direct activation of PSCs, we used fluorescence video-microscopy in the real-time mode to measure PNU 282987-induced [Ca2+ ]i transients from Fluo-4 NW loaded PSCs in non-stimulated preparations. The α7nAChR agonist, PNU 282987, decreased nerve-evoked diaphragm tetanic contractions. PNU 282987-induced inhibition was mimicked by neostigmine and results from the reduction of ACh exocytosis measured as decreases in [3 H]ACh release and FM4-64 fluorescent dye unloading. Methyllycaconitine blockage of α7nAChR and the fluoroacetate gliotoxin both prevented inhibition of nerve-evoked ACh release and PSCs [Ca2+ ]i transients triggered by PNU 282987 and neostigmine. Adenosine deamination, inhibition of the ENT1 nucleoside outflow, and blockage of A1 receptors prevented PNU 282987-induced inhibition of transmitter release. Data suggest that α7nAChR controls tetanic-induced ACh spillover from the neuromuscular synapse by promoting adenosine outflow from PSCs via ENT1 transporters and retrograde activation of presynaptic A1 inhibitory receptors.

Spinal muscular atrophy: diagnosis, treatment and future prospects.

OBJECTIVE: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. SOURCES: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SUMMARY OF THE FINDINGS: SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. CONCLUSIONS: SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.

Atrofia muscular espinhal: diagnóstico, tratamento e perspectivas futuras / Spinal muscular atrophy: diagnosis, treatment and future prospects

OBJETIVO: Relatar as recentes descobertas genéticas e moleculares, juntamente com as perspectivas futuras, para o tratamento da atrofia muscular espinhal, auxiliando, dessa forma, os profissionais da área da saúde a fazerem um rápido diagnóstico e proporcionarem um suporte terapêutico correto e precoce. FONTES DOS DADOS: As informações foram coletadas a partir de artigos científicos publicados nas duas últimas décadas, pesquisados nas bases de dados SciELO, PubMed e MEDLINE. SÍNTESE DOS DADOS: A atrofia muscular espinhal é uma doença neurodegenerativa com herança genética autossômica recessiva. É causada por uma deleção homozigótica do gene de sobrevivência do motoneurônio. Essa alteração genética resulta na redução dos níveis da proteína de sobrevivência do motoneurônio, levando à degeneração de motoneurônios alfa da medula espinhal, o que resulta em fraqueza e paralisia muscular proximal progressiva simétrica. Sabe-se que alguns cuidados básicos referentes à nutrição, respiração e fisioterapia podem ser importantes para retardar o progresso da doença e prolongar a vida dos pacientes. Vários medicamentos estão sendo testados, alguns novos, outros já conhecidos, como o ácido valproico, sendo que a paralisia pode ser estacionada, mas não revertida. CONCLUSÕES: A atrofia muscular espinhal é uma desordem de difícil diagnóstico, por ser pouco conhecida, e de tratamento ainda incerto. Os tratamentos farmacológicos e as terapias de suporte existentes ainda não são capazes de recuperar os motoneurônios ou as células musculares que já foram perdidos, mas têm o objetivo de retardar o progresso da doença e melhorar a função muscular residual dos pacientes, bem como oferecer uma melhor qualidade e expectativa de vida.

OBJECTIVE: To report on recent genetic and molecular discoveries and on future prospects for the treatment of spinal muscular atrophy (SMA), thereby helping healthcare professionals to make a quick diagnosis and provide appropriate and timely therapeutic support. SOURCES: Information was collected from scientific articles published in the last 2 decades, retrieved from the databases SciELO, PubMed, and MEDLINE. SUMMARY OF THE FINDINGS: SMA is a neurodegenerative disorder with autosomal recessive genetic heredity. It is caused by a homozygous deletion of the survival motor neuron (SMN1) gene. This genetic alteration results in reduced levels of the SMN protein, leading to degeneration of alpha motor neurons of the spinal cord and resulting in muscle weakness and progressive symmetrical proximal paralysis. It is known that basic nutritional and respiratory care and physiotherapy can be important to delaying disease progression and prolonging patients' lives. Several drugs are being tested, some new, others, such as valproic acid, already known; paralysis can be halted, but not reversed. CONCLUSIONS: SMA is a difficult to diagnose disorder, because it is little known, and treatment is uncertain. Pharmacological treatments and supportive therapies are not yet able to recover motor neurons or muscle cells that have already been lost, but are aimed at delaying disease progression and improving patients' residual muscle function, as well as offering better quality of life and life expectancy.