Acute administration of ucf-101 ameliorates the locomotor impairments induced by a traumatic spinal cord injury.

Secondary death of neural cells plays a key role in the physiopathology and the functional consequences of traumatic spinal cord injury (SCI). Pharmacological manipulation of cell death pathways leading to the preservation of neural cells is acknowledged as a main therapeutic goal in SCI. In the present work, we hypothesize that administration of the neuroprotective cell-permeable compound ucf-101 will reduce neural cell death during the secondary damage of SCI, increasing tissue preservation and reducing the functional deficits. To test this hypothesis, we treated mice with ucf-101 during the first week after a moderate contusive SCI. Our results reveal that ucf-101 administration protects neural cells from the deleterious secondary mechanisms triggered by the trauma, reducing the extension of tissue damage and improving motor function recovery. Our studies also suggest that the effects of ucf-101 may be mediated through the inhibition of HtrA2/OMI and the concomitant increase of inhibitor of apoptosis protein XIAP, as well as the induction of ERK1/2 activation and/or expression. In vitro assays confirm the effects of ucf-101 on both pathways as well as on the reduction of caspase cascade activation and apoptotic cell death in a neuroblastoma cell line. These results suggest that ucf-101 can be a promising therapeutic tool for SCI that deserves more detailed analyses.

Los MicroRNAs neuroprotectores en el daño secundario de la lesión medular traumática / Neuroprotective microRNAs in the secondary damage of the traumatic spinal cord injury

Objetivo: Identificar microRNAs cuyos niveles varían específicamente tras una lesión medular traumática. Material y método: en un modelo animal murino (Rattus norvegicus (rata) de la cepa Wistar) se realizó lesión medular mediante contusión, y los fragmentos medulares fueron extraídos a las 24 horas, 3 días y 7 días postlesión. Los patrones de expresión de los animales lesionados se compararon con animales control en los que se realizó laminectomía sin lesión y con un grupo de animales en los que no se realizó ninguna cirugía anterior a la extracción. Resultados: Entre los microRNAs que mostraron una alteración tras la lesión de la médula espinal destaca miR-21, el cual ha sido implicado en el proceso de apoptosis en el sistema nervioso. Conclusión: la lesión de la médula espinal produce alteraciones importantes en los niveles de expresión de microRNAs que participan en los procesos que acontecen en dicha lesión, tales como apoptosis e inflamación (AU)

Aim: Identify microRNAs whose levels change specifically after traumatic spinal cord injury. Materials and methods: in a murine animal model (Rattus norvegicus (rat) Wistar), spinal cord injury was induced by contusion and the medullar fragments were extracted 24 hours, 3 days and 7 days post-injury. The expression patterns of the injured animals were compared with animals that had laminectomy without injury and animals that had no surgery before the extraction. Result: among the microRNAs that change after spinal cord injury it is miR-21 that has been implicated in apoptosis in the nervous system. Conclusion: spinal cord injury causes dramatic changes in the microRNA expression pattern that have a role in the proccesses that take place in the injury as apoptosis and inflamation (AU)

Elevated pressure triggers a physiological release of ATP from the retina: Possible role for pannexin hemichannels.

Increased hydrostatic pressure can damage neurons, although the mechanisms linking pressure to neurochemical imbalance or cell injury are not fully established. Throughout the body, mechanical perturbations such as shear stress, cell stretching, or changes in pressure can lead to excessive release of ATP. It is thus possible that increased pressure across neural tissues triggers an elevated release of ATP into extracellular space. As stimulation of the P2X(7) receptor for ATP on retinal ganglion cells leads to elevation of intracellular calcium and excitotoxic death, we asked whether increased levels of extracellular ATP accompanied an elevation in pressure across the retina. The hydrostatic pressure surrounding bovine retinal eyecups was increased and the ATP content of the vitreal compartment adjacent to the retina was determined. A step increase of only 20 mm Hg induced a threefold increase in the vitreal ATP concentration. The ATP levels correlated closely with the degree of pressure increase over 20-100 mm Hg. The increase was transient at lower pressures but sustained at higher pressures. The rise in vitreal ATP was the same regardless of whether nitrogen or air was used to increase pressure, implying changes in oxygen partial pressure did not contribute. Lactate dehydrogenase activity was not affected by pressure, ruling out a substantial contribution from cell lysis. The ATP increase was largely inhibited by either 30 muM 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) or 10 muM carbenoxolone (CBX). While this pharmacological profile is consistent with physiological release of ATP through pannexins hemichannels, a contribution from anion channels, vesicular release or other mechanisms cannot be ruled out. In conclusion, a step elevation in pressure leads to a physiologic increase in the levels of extracellular ATP bathing retinal neurons. This excess extracellular ATP may link increased pressure to the death of ganglion cells in acute glaucoma, and suggests a possible role for ATP in the neuronal damage accompanying increased intracranial pressure.

Ionic dependence of the velocity of release of ATP from permeabilized cholinergic synaptic vesicles.

Evidence is provided to show that synaptic vesicles have an internal matrix. Suspensions of cholinergic synaptic vesicles isolated from the electric organ of Torpedo marmorata fish were permeabilized in solutions containing low concentrations of Na(+) or Ca(2+). The release of ATP from the vesicular matrix was 10 times more effective with Ca(2+) than with Na(+). We ascertained whether these two cations induced a different velocity of release of ATP from the matrix. The release of ATP was monitored with the chemiluminescent reaction of luciferin-luciferase. The light signal generated was the result of the kinetics of ATP release of the enzymatic reaction. To overcome the kinetics of the enzymatic reaction, the light records were deconvoluted. The actual kinetics of ATP release of vesicles containing Na(+) or Ca(2+) were coincident. To validate this result, comparison was made with ATP release from intact nerve terminals which were already deconvoluted. The results show that the real time course of release is longer than that obtained from synaptic vesicles. This was as expected given that the release of neurotransmitters is due to successive molecular steps of synaptic vesicle exocytosis.

Purines, the carotid body and respiration.

The carotid body is essential to detecting levels of oxygen in the blood and initiating the compensatory response. Increasing evidence suggests that the purines ATP and adenosine make a key contribution to this signaling by the carotid body. The glomus cells release ATP in response to hypoxia. This released ATP can stimulate P2X receptors on the carotid body to elevate intracellular Ca(2+) and to produce an excitatory response. This released ATP can be dephosphorylated to adenosine by a series of extracellular enzymes, which in turn can stimulate A(1), A(2A) and A(2B) adenosine receptors. Levels of extracellular adenosine can also be altered by membrane transporters. Endogenous adenosine stimulates these receptors to increase the ventilation rate and may modulate the catecholamine release from the carotid sinus nerve. Prolonged hypoxic challenge can alter the expression of purinergic receptors, suggesting a role in the adaptation. This review discusses evidence for a key role of ATP and adenosine in the hypoxic response of the carotid body, and emphasizes areas of new contributions likely to be important in the future.