Experimental neurology
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Experimental neurology · Jul 2020
Low-pressure fluid percussion minimally adds to the sham craniectomy-induced neurobehavioral changes: Implication for experimental traumatic brain injury model.
Modeling experimental traumatic brain injury (TBI) in rodents is necessarily required to understand the pathophysiological and neurobehavioral consequences of neurotrauma. Numerous models have been developed to study experimental TBI. Fluid percussion injury (FPI) is the most extensively used model to represent clinical phenotypes. ⋯ Our results indicate that sham craniectomy itself is enough to cause TBI like characteristics, and thus fluid percussion at mild pressure is minimally additive with craniectomy. Considering the method as a mixed (focal & diffused) injury model, the 'net neurotrauma severity' should be compared with naïve control instead of the sham as it is an outcome of cumulative damage due to fluid pressure and craniectomy. Nevertheless, to understand the long term consequences of neurotrauma, the extent of recovery in surgical sham may separately be quantified.
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Experimental neurology · May 2020
Upregulation of transcription factor 4 downregulates NaV1.8 expression in DRG neurons and prevents the development of rat inflammatory and neuropathic hypersensitivity.
The voltage sodium channel 1.8 (NaV1.8) in the dorsal root ganglion (DRG) neurons contributes to the initiation and development of chronic inflammatory and neuropathic pain. However, an effective intervention on NaV1.8 remains to be studied in pre-clinical research and clinical trials. In this study, we aimed to investigate whether transcription factor 4 (TCF4) overexpression represses NaV1.8 expression in DRG neurons, thus preventing the development of chronic pain. ⋯ We showed that the intrathecal delivery of TCF4 overexpression virus significantly repressed the increase of NaV1.8 and prevented the development of hyperalgesia in rats. Moreover, we confirmed the efficient role of an overexpressed TCF4 in preventing the CFA- and SNI-induced neuronal hyperexcitability by calcium imaging. Our results suggest that attenuating the dysregulation of NaV1.8 by targeting TCF4 may be a novel therapeutic strategy for chronic inflammatory and neuropathic pain.
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Experimental neurology · Mar 2020
ReviewPathogenesis of platinum-induced peripheral neurotoxicity: Insights from preclinical studies.
One of the most relevant dose-limiting adverse effects of platinum drugs is the development of a sensory peripheral neuropathy that highly impairs the patients' quality of life. Nowadays there are no available efficacy strategies for the treatment of platinum-induced peripheral neurotoxicity (PIPN), and the only way to prevent its development and progression is by reducing the dose of the cytostatic drug or even withdrawing the chemotherapy regimen. This clinical issue has been the main focus of hundreds of preclinical research works during recent decades. ⋯ This mechanism of DRG sensory neurons cell death is triggered by the nuclear and mitochondrial DNA platination together with the increase of the oxidative cellular status induced by the depletion of cytoplasmic antioxidant mechanisms. However, since there has been no successful transfer of preclinical results to clinical practise in terms of therapeutic approaches, some mechanisms of PIPN pathogenesis still remain to be elucidated. This review is focused on the pathogenic mechanisms underlying PIPN described up to now, provided by the critical analysis of in vitro and in vivo models.
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Experimental neurology · Mar 2020
Acute upregulation of bone morphogenetic protein-4 regulates endogenous cell response and promotes cell death in spinal cord injury.
Traumatic spinal cord injury (SCI) elicits a cascade of secondary injury mechanisms that induce profound changes in glia and neurons resulting in their activation, injury or cell death. The resultant imbalanced microenvironment of acute SCI also negatively impacts regenerative processes in the injured spinal cord. Thus, it is imperative to uncover endogenous mechanisms that drive these acute injury events. ⋯ BMP4 also enhances the production of inhibitory chondroitin sulfate proteoglycans (CSPGs) in activated astrocytes in vitro and after SCI. Interestingly, our work reveals that despite the beneficial effects of BMP inhibition in acute SCI, neither noggin nor LDN193189 treatment resulted in long-term functional recovery. Collectively, our findings suggest a role for BMP4 in regulating acute secondary injury mechanisms following SCI, and a potential target for combinatorial approaches to improve endogenous cell response and remyelination.
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Experimental neurology · Feb 2020
Increased severity of the CHIMERA model induces acute vascular injury, sub-acute deficits in memory recall, and chronic white matter gliosis.
Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head and contribute to disability throughout the injury severity spectrum. CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) is a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter gliosis and axonal damage. ⋯ Memory deficits were evident at 30 d and resolved by 60 d. Intriguingly, white matter injury was not remarkable at acute time points but evolved over time, with white matter gliosis being most extensive at 60 d. Interface-assisted CHIMERA thus enables experimental modeling of distinct endophenotypes of TBI that include acute vascular and grey matter injury in addition to chronic evolution of white matter damage, similar to the natural history of human TBI.