RESUMO
Neuropathic pain (NP) following a spinal cord injury (SCI) is often hard to control and therapies should be focused on the physical, psychological, behavioral, social, and environmental factors that may contribute to chronic sensory symptoms. Novel therapeutic treatments for NP management should be based on the combination of pharmacological and nonpharmacological options. Some of them are addressed in this review with a focus on mechanisms and novel treatments. Several reports demonstrated an aberrant expression of non-coding RNAs (ncRNAs) that may represent key regulatory factors with a crucial role in the pathophysiology of NP and as potential diagnostic biomarkers. This review analyses the latest evidence for cellular and molecular mechanisms associated with the role of circular RNAs (circRNAs) in the management of pain after SCI. Advantages in the use of circRNA are their stability (up to 48 h), and specificity as sponges of different miRNAs related to SCI and nerve injury. The present review discusses novel data about deregulated circRNAs (up or downregulated) that sponge miRNAs, and promote cellular and molecular interactions with mRNAs and proteins. This data support the concept that circRNAs could be considered as novel potential therapeutic targets for NP management especially after spinal cord injuries.
Assuntos
MicroRNAs , Neuralgia , Traumatismos da Medula Espinal , Humanos , RNA Circular/genética , Manejo da Dor , Traumatismos da Medula Espinal/metabolismo , MicroRNAs/genética , Neuralgia/genéticaRESUMO
Spinal Cord Injury (SCI) can elicit a progressive loss of nerve cells promoting disability, morbidity, and even mortality. Despite different triggering mechanisms, a cascade of molecular events involving complex gene alterations and activation of the neuroimmune system influence either cell damage or repair. Effective therapies to avoid secondary mechanisms underlying SCI are still lacking. The recent progression in circular RNAs (circRNAs) research has drawn increasing attention and opened a new insight on SCI pathology. circRNAs differ from traditional linear RNAs and have emerged as the active elements to regulate gene expression as well as to facilitate the immune response involved in pathophysiology-related conditions. In this review, we focus on the impact and possible close relationship of circRNAs with pathophysiological mechanisms following SCI, where circRNAs could be the key transcriptional regulatory molecules to define neuronal death or survival. Advances in circRNAs research provide new insight on potential biomarkers and effective therapeutic targets for SCI patients.
RESUMO
The axolotl (Ambystoma mexicanum) has been a widely studied organism due to its capacity to regenerate most of its cells, tissues and whole-body parts. Since its genome was sequenced, several molecular tools have been developed to study the mechanisms behind this outstanding and extraordinary ability. The complexity of its genome due to its sheer size and the disproportionate expansion of a large number of repetitive elements, may be a key factor at play during tissue remodeling and regeneration mechanisms. Transcriptomic analysis has provided information to identify candidate genes networks and pathways that might define successful or failed tissue regeneration. Nevertheless, the epigenetic machinery that may participate in this phenomenon has largely not been studied. In this review, we outline a broad overview of both genetic and epigenetic molecular processes related to regeneration in axolotl, from the macroscopic to the molecular level. We also explore the epigenetic mechanisms behind regenerative pathways, and its potential importance in future regeneration research. Altogether, understanding the genomics and global regulation in axolotl will be key for elucidating the special biology of this organism and the fantastic phenomenon that is regeneration.
Assuntos
Ambystoma mexicanum , Epigenômica , Regeneração/genética , Ambystoma mexicanum/genética , Ambystoma mexicanum/crescimento & desenvolvimento , Animais , Extremidades , Perfilação da Expressão Gênica , Genoma , GenômicaRESUMO
Any spinal cord injury carries the potential for persistent disability affecting motor, sensory and autonomic functions. To prevent this outcome, it is highly desirable to block a chain of deleterious reactions developing in the spinal areas immediately around the primary lesion. Thus, early timing of pharmacological neuroprotection should be one major strategy whose impact may be first studied with preclinical models. Using a simple in vitro model of the rat spinal cord it is possible to mimic pathological processes like excitotoxicity that damages neurons because of excessive glutamate receptor activation due to injury, or hypoxic/dysmetabolic insult that preferentially affects glia following vascular dysfunction. While ongoing research is exploring the various components of pathways leading to cell death, current treatment principally relies on the off-label use of riluzole (RLZ) or methylprednisolone sodium succinate (MPSS). The mechanism of action of these drugs is diverse as RLZ targets mainly neurons and MPSS targets glia. Even when applied after a transient excitotoxic stimulus, RLZ can provide effective prevention of secondary excitotoxic damage to premotoneurons, although not to motoneurons that remain very vulnerable. This observation indicates persistent inability to express locomotor activity despite pharmacological treatment conferring some histological protection. MPSS can protect glia from dysmetabolic insult, yet it remains poorly effective to prevent neuronal death. In summary, it appears that these pharmacological agents can produce delayed protection for certain cell types only, and that their combined administration does not provide additional benefit. The search should continue for better, mechanism-based neuroprotective agents.
Assuntos
Anti-Inflamatórios/uso terapêutico , Metilprednisolona/uso terapêutico , Neuroproteção/fisiologia , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Anti-Inflamatórios/farmacologia , Humanos , Metilprednisolona/farmacologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Riluzol/farmacologia , Traumatismos da Medula Espinal/metabolismoRESUMO
Synaptic cotransmission is the ability of neurons to use more than one transmitter to convey synaptic signals. Cotransmission was originally described as the presence of a classic transmitter, which conveys main signal, along one or more cotransmitters that modulate transmission, later on, it was found cotransmission of classic transmitters. It has been generally accepted that neurons store and release the same set of transmitters in all their synaptic processes. However, some findings that show axon endings of individual neurons storing and releasing different sets of transmitters, are not in accordance with this assumption, and give support to the hypothesis that neurons can segregate transmitters to different synapses. Here, we review the studies showing segregation of transmitters in invertebrate and mammalian central nervous system neurons, and correlate them with our results obtained in sympathetic neurons. Our data show that these neurons segregate even classic transmitters to separated axons. Based on our data we suggest that segregation is a plastic phenomenon and responds to functional synaptic requirements, and to 'environmental' cues such as neurotrophins. We propose that neurons have the machinery to guide the different molecules required in synaptic transmission through axons and sort them to different axon endings. We believe that transmitter segregation improves neuron interactions during cotransmission and gives them selective and better control of synaptic plasticity.