ABSTRACT
The α-conotoxins are peptide toxins that are identified from the venom of marine cone snails and they hold outstanding potency on various subtypes of nicotinic acetylcholine receptors (nAChRs). nAChRs have an important role in regulating transmitter release, cell excitability, and neuronal integration, so nAChR dysfunctions have been involved in a variety of severe pathologies. Four types of α-3/5 conotoxins MI, MIA, MIB and MIC have been found from Conus magus. Among them, the activity and selectivity of MIA and MIB have not been well studied. In this study, four α-3/5 conotoxins MI, MIA, MIB and MIC were synthesized by solid peptide synthesis method, and the bioactivities of them were screened by double electrode voltage clamp electrophysiology. The results showed that MIA and MIB selectively inhibited muscle type acetylcholine receptors with IC50 values of 14.45 and 72.78 nmol·L-1, respectively, which are slightly weaker than MI and MIC. Molecular docking results have shown MIA and MIB interact with muscle-type nAChRs with similar mechanism. The reasons for activity differences may relate to the size of the N-terminal amino acids. Together, the conotoxins MIA and MIB may have the potential to develop as a tool for detect the function of muscle type nAChRs, as well as the diagnosis or treat of related diseases.
ABSTRACT
O bloqueio dos canais para cálcio dependentes de voltagem é uma estratégia importante no tratamento do trauma medular, pois previne o influxo exacerbado do cálcio que participa ativamente em processos neurodegenerativos agudos, resultando em neuroproteção com melhora das funções neurológica. Dentre esses bloqueadores, as toxinas de caramujos marinhos são peptídeos com adequada estabilidade estrutural, estudadas pelas ações específicas em canais iônicos e receptores que interferem diretamente na liberação de neurotransmissores e na neuromodulação dos neurônios motores e sensitivos da medula espinal. Elas já são utilizadas no tratamento de desordens neurológicas e mostram-se promissoras no desenvolvimento de novas terapias para o trauma medular. Portanto, objetivou-se discorrer sobre a fisiopatologia do trauma medular e a possível utilização terapêutica das toxinas de caramujo marinho, atuantes nos principais canais para cálcio dependentes de voltagem.
Blocking voltage dependent calcium channels is an important strategy in acute spinal trauma treatment, because it prevents the exacerbated calcium influx which participates actively in acute neurodegenerative processes, resulting in neuroprotection with improvement of neurological and electrophysiological functions. The cone snail toxins are peptides with adequate structural stability, which have been studied by specific actions on ion channels and receptors that directly interfering in the release of neurotransmitters and neuromodulation of sensory and motor neurons of the spinal cord. They are already used in the treatment of neurological disorders and appear to be promising in the development of new therapies for spinal trauma. Therefore, it was aimed to discuss the pathophysiology of spinal cord trauma, and possible therapeutic use of marine snail toxins that acts in voltage-dependent calcium channels.
ABSTRACT
Calcium channel blockers such as conotoxins have shown a great potential to reduce brain and spinal cord injury. MVIIC neuroprotective effects analyzed in in vitro models of brain and spinal cord ischemia suggest a potential role of this toxin in preventing injury after spinal cord trauma. However, previous clinical studies with MVIIC demonstrated that clinical side effects might limit the usefulness of this drug and there is no research on its systemic effects. Therefore, the present study aimed to investigate the potential toxic effects of MVIIC on organs and to evaluate clinical and blood profiles of rats submitted to spinal cord injury and treated with this marine toxin. Rats were treated with placebo or MVIIC (at doses of 15, 30, 60 or 120 pmol) intralesionally following spinal cord injury. Seven days after the toxin administration, kidney, brain, lung, heart, liver, adrenal, muscles, pancreas, spleen, stomach, and intestine were histopathologically investigated. In addition, blood samples collected from the rats were tested for any hematologic or biochemical changes.
Subject(s)
Animals , Rats , Bone Marrow , Calcium Channel Blockers/analysis , Cerebrum/anatomy & histology , Conotoxins/analysis , Wounds and Injuries , RatsABSTRACT
Calcium channel blockers such as conotoxins have shown a great potential to reduce brain and spinal cord injury. MVIIC neuroprotective effects analyzed in in vitro models of brain and spinal cord ischemia suggest a potential role of this toxin in preventing injury after spinal cord trauma. However, previous clinical studies with MVIIC demonstrated that clinical side effects might limit the usefulness of this drug and there is no research on its systemic effects. Therefore, the present study aimed to investigate the potential toxic effects of MVIIC on organs and to evaluate clinical and blood profiles of rats submitted to spinal cord injury and treated with this marine toxin. Rats were treated with placebo or MVIIC (at doses of 15, 30, 60 or 120 pmol) intralesionally following spinal cord injury. Seven days after the toxin administration, kidney, brain, lung, heart, liver, adrenal, muscles, pancreas, spleen, stomach, and intestine were histopathologically investigated. In addition, blood samples collected from the rats were tested for any hematologic or biochemical changes.