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Nistri A.,International School for Advanced Studies | Nistri A.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory
European Journal of Physical and Rehabilitation Medicine | Year: 2012

An acute lesion to the spinal cord triggers complex mechanisms responsible for amplification of the initial damage and its chronicity. In vitro preparations of the rodent spinal cord retain the intrinsic ability to produce locomotor-like discharges from lumbar ventral roots and, thus, offer the opportunity to study the still unclear process of lesion progression in relation to cell number and topography. In addition, these models enable a detailed approach to the molecular mechanisms of damage and to pharmacological tools to counteract them. Using the rat spinal cord in vitro, our laboratory has shown how to reliably produce discrete lesions by applying the glutamate agonist kainate that evokes delayed neuronal loss via a non-apoptotic cell death mechanism termed parthanatos. Parthanatos is believed to be due to mitochondrial damage and exhaustion of cell energy stores caused by hyperactivation of enzymatic systems initially set to repair DNA damage. Locomotor network activity is irreversibly destroyed by kainate in a virtually all-or-none manner, suggesting destruction of a highly-vulnerable cell population crucial for the expression of locomotion. Hypoxic challenge to the spinal cord together with toxic radicals primarily damages white matter cells with deficit (without full suppression) of locomotor network function, while neurons are less vulnerable. Pharmacological agents to inhibit different targets involved in the early pathophysiology of spinal injury provided limited success, indicating that novel approaches based on newly identified steps in the biochemical cascade leading to cell death should be investigated for their potential to improve the outcome of spinal cord injury. Source


Cifra A.,International School for Advanced Studies | Mazzone G.L.,International School for Advanced Studies | Nistri A.,International School for Advanced Studies | Nistri A.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory
Neuroscientist | Year: 2013

Amyotrophic lateral sclerosis (Lou Gehrig's disease) is a devastating neurodegenerative disorder for which the only licensed treatment is riluzole. Although riluzole clinical efficacy is rather limited, its use has important implications for identifying those parameters that might improve its clinical benefits (dose, timing, disease stage) and for its offlabel administration in other neurodegenerative diseases, such as spinal cord injury. Studies of riluzole also have an intrinsically heuristic value to unveil mechanisms regulating the excitability of brain and spinal neurons because this drug is a pharmacological tool to probe the function of certain ion channels, or to study neurotransmitter release processes, and intracellular neuroprotective pathways. The present review focuses on how riluzole acts on brain and spinal neurons within motor networks, what mechanisms can be deduced from its effects, and what conditions may favor its use to contrast neurodegeneration or to ameliorate late symptoms like spasticity. Taking as an example the experimental neurodegeneration caused by overactivation of glutamatergic synapses (excitotoxicity), it seems likely that protection of motor networks by riluzole involves selected administration timing and dosing to target processes for releasing glutamate from very active synapses or for dampening repetitive firing by hyperfunctional motor cells. © The Author(s) 2012. Source


Dingu N.,International School for Advanced Studies | Dingu N.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory | Deumens R.,Catholic University of Louvain | Taccola G.,International School for Advanced Studies | Taccola G.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory
Neuromodulation | Year: 2016

Objectives Investigate whether electrical stimulation of the spinal cord adapted to trigger locomotor patterns additionally influences dorsal horn networks. Materials and Methods An in vitro model of isolated neonatal rat spinal cord was used to repetitively deliver electrical stimuli to lumbar dorsal roots and record from homolateral lumbar dorsal roots and ventral roots. Results Repetitive electrical lumbar dorsal root stimulation can affect both locomotor rhythms derived from ventral neuronal circuits and activity from dorsal neuronal circuits. Conclusion These data suggest that neuro-electrostimulation protocols can simultaneously activate functionally distinct spinal neuronal circuits. © 2015 International Neuromodulation Society. Source


Mladinic M.,International School for Advanced Studies | Mladinic M.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory | Mladinic M.,University of Rijeka | Nistri A.,International School for Advanced Studies | Nistri A.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory
Frontiers in Neuroengineering | Year: 2013

Microelectrode arrays (MEAs) represent an important tool to study the basic characteristics of spinal networks that control locomotion in physiological conditions. Fundamental properties of this neuronal rhythmicity like burst origin, propagation, coordination and resilience can, thus, be investigated at multiple sites within a certain spinal topography and neighbouring circuits. A novel challenge will be to apply this technology to unveil the mechanisms underlying pathological processes evoked by spinal cord injury. To achieve this goal, it is necessary to fully identify spinal networks that make up the locomotor central pattern generator (CPG) and to understand their operational rules. In this review, the use of isolated spinal cord preparations from rodents, or organotypic spinal slice cultures is discussed to study rhythmic activity. In particular, this review surveys our recently developed in vitro models of spinal cord injury by evoking excitotoxic (or even hypoxic/dysmetabolic) damage to spinal networks and assessing their impact on rhythmic activity and cell survival. These pathological processes which evolve via different cell death mechanisms are discussed as a paradigm to apply MEA recording for detailed mapping of the functional damage and its time-dependent evolution. © 2013 Mladinic and Nistri. Source


Bianchetti E.,International School for Advanced Studies | Mladinic M.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory | Mladinic M.,University of Rijeka | Nistri A.,International School for Advanced Studies | Nistri A.,SPINAL Spinal Person Injury Neurorehabilitation Applied Laboratory
Cell Death and Disease | Year: 2013

New spinal cord injury (SCI) cases are frequently due to non-traumatic causes, including vascular disorders. To develop mechanism-based neuroprotective strategies for acute SCI requires full understanding of the early pathophysiological changes to prevent disability and paralysis. The aim of our study was to identify the molecular and cellular mechanisms of cell death triggered by a pathological medium (PM) mimicking ischemia in the rat spinal cord in vitro. We previously showed that extracellular Mg2+ (1 mM) worsened PM-induced damage and inhibited locomotor function. The present study indicated that 1 h of PM+Mg2+ application induced delayed pyknosis chiefly in the spinal white matter via overactivation of poly (ADP-ribose) polymerase 1 (PARP1), suggesting cell death mediated by the process of parthanatos that was largely suppressed by pharmacological block of PARP-1. Gray matter damage was less intense and concentrated in dorsal horn neurons and motoneurons that became immunoreactive for the mitochondrial apoptosis-inducing factor (the intracellular effector of parthanatos) translocated into the nucleus to induce chromatin condensation and DNA fragmentation. Immunoreactivity to TRPM ion channels believed to be involved in ischemic brain damage was also investigated. TRPM2 channel expression was enhanced 24 h later in dorsal horn and motoneurons, whereas TRPM7 channel expression concomitantly decreased. Conversely, TRPM7 expression was found earlier (3 h) in white matter cells, whereas TRPM2 remained undetectable. Simulating acute ischemic-like damage in vitro in the presence of Mg2+ showed how, during the first 24 h, this divalent cation unveiled differential vulnerability of white matter cells and motoneurons, with distinct changes in their TRPM expression. © 2013 Macmillan Publishers Limited All rights reserved. Source

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