Cyclosporine as Therapy for Traumatic Brain Injury
AbstractDrug development in traumatic brain injury (TBI) has been impeded by the complexity and heterogeneity of the disease pathology, as well as limited understanding of the secondary injury cascade that follows the initial trauma. As a result, patients with TBI have an unmet need for effective pharmacological therapies. One promising drug candidate is cyclosporine, a polypeptide traditionally used to achieve immunosuppression in transplant recipients. Cyclosporine inhibits mitochondrial permeability transition, thereby reducing secondary brain injury, and has shown neuroprotective effects in multiple preclinical models ...
Source: Neurotherapeutics - August 10, 2023 Category: Neurology Source Type: research
Dimethyl Fumarate or Teriflunomide for Relapsing –Remitting Multiple Sclerosis: A Meta-analysis of Post-marketing Studies
AbstractIn the absence of head-to-head comparison trials, we aimed to compare the effectiveness of two largely prescribed oral platform disease-modifying treatments for relapsing –remitting multiple sclerosis, namely, dimethyl fumarate (DMF) and teriflunomide (TRF). We searched scientific databases to identify real-world studies reporting a direct comparison of DMF versus TRF. We fitted inverse-variance weighted meta-analyses with random effects models to estimate the risk ratio (RR) of relapse, confirmed disability worsening (CDW), and treatment discontinuation. Quantitative synthesis was accomplished on 14 articles yie...
Source: Neurotherapeutics - August 1, 2023 Category: Neurology Source Type: research
Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy
AbstractMetachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that sulfatide induces demyelination in a concentration-dependent manner. Interestingly, our novel data demonstrate that sulfatide-induced demyelination is underpinned by PARP-1 activati...
Source: Neurotherapeutics - July 31, 2023 Category: Neurology Source Type: research
Increasing Rigor of Preclinical Research to Maximize Opportunities for Translation
AbstractThe use of animal models in pre-clinical research has significantly broadened our understanding of the pathologies that underlie traumatic brain injury (TBI)-induced damage and deficits. However, despite numerous pre-clinical studies reporting the identification of promising neurotherapeutics, translation of these therapies to clinical application has so far eluded the TBI research field. A concerted effort to address this lack of translatability is long overdue. Given the inherent heterogeneity of TBI and the replication crisis that continues to plague biomedical research, this is a complex task that will require ...
Source: Neurotherapeutics - July 31, 2023 Category: Neurology Source Type: research
Olaparib Attenuates Demyelination and Neuroinflammation in an Organotypic Slice Culture Model of Metachromatic Leukodystrophy
AbstractMetachromatic leukodystrophy (MLD) is a severe demyelinating, autosomal recessive genetic leukodystrophy. The disease is underpinned by mutations in the arylsulfatase A gene (ARSA), resulting in deficient activity of the arylsulfatase A lysosomal enzyme and consequential accumulation of galactosylceramide-3-O-sulfate (sulfatide) in the brain. Using an ex vivo murine-derived organotypic cerebellar slice culture model, we demonstrate that sulfatide induces demyelination in a concentration-dependent manner. Interestingly, our novel data demonstrate that sulfatide-induced demyelination is underpinned by PARP-1 activati...
Source: Neurotherapeutics - July 31, 2023 Category: Neurology Source Type: research
Increasing Rigor of Preclinical Research to Maximize Opportunities for Translation
AbstractThe use of animal models in pre-clinical research has significantly broadened our understanding of the pathologies that underlie traumatic brain injury (TBI)-induced damage and deficits. However, despite numerous pre-clinical studies reporting the identification of promising neurotherapeutics, translation of these therapies to clinical application has so far eluded the TBI research field. A concerted effort to address this lack of translatability is long overdue. Given the inherent heterogeneity of TBI and the replication crisis that continues to plague biomedical research, this is a complex task that will require ...
Source: Neurotherapeutics - July 31, 2023 Category: Neurology Source Type: research
A Novel Drosophila-based Drug Repurposing Platform Identified Fingolimod As a Potential Therapeutic for TDP-43 Proteinopathy
AbstractPathogenic changes to TAR DNA-binding protein 43 (TDP-43) leading to alteration of its homeostasis are a common feature shared by several progressive neurodegenerative diseases for which there is no effective therapy. Here, we developedDrosophila lines expressing either wild type TDP-43 (WT) or that carrying an Amyotrophic Lateral Sclerosis /Frontotemporal Lobar Degeneration-associating G384C mutation that recapitulate several aspects of the TDP-43 pathology. To identify potential therapeutics for TDP-43-related diseases, we implemented a drug repurposing strategy that involved three consecutive steps. Firstly, we ...
Source: Neurotherapeutics - July 26, 2023 Category: Neurology Source Type: research
Management Strategies Based on Multi-Modality Neuromonitoring in Severe Traumatic Brain Injury
AbstractSecondary brain injury after neurotrauma is comprised of a host of distinct, potentially concurrent and interacting mechanisms that may exacerbate primary brain insult. Multimodality neuromonitoring is a method of measuring multiple aspects of the brain in order to understand the signatures of these different pathomechanisms and to detect, treat, or prevent potentially reversible secondary brain injuries. The most studied invasive parameters include intracranial pressure (ICP), cerebral perfusion pressure (CPP), autoregulatory indices, brain tissue partial oxygen tension, and tissue energy and metabolism measures s...
Source: Neurotherapeutics - July 25, 2023 Category: Neurology Source Type: research
Intersectionality in Alzheimer ’s Disease: The Role of Female Sex and Black American Race in the Development and Prevalence of Alzheimer’s Disease
AbstractIt is well known that vascular factors and specific social determinants of health contribute to dementia risk and that the prevalence of these risk factors differs according to race and sex. In this review, we discuss the intersection of sex and race, particularly female sex and Black American race. Women, particularly Black women, have been underrepresented in Alzheimer ’s disease clinical trials and research. However, in recent years, the number of women participating in clinical research has steadily increased. A greater prevalence of vascular risk factors such as hypertension and type 2 diabetes, coupled with...
Source: Neurotherapeutics - July 25, 2023 Category: Neurology Source Type: research
Anti-Amyloid Immunotherapies for Alzheimer ’s Disease: A 2023 Clinical Update
AbstractThe amyloid cascade hypothesis is a useful framework for therapeutic development in Alzheimer ’s disease (AD). Amyloid b1-42 (A β) has been the main target of experimental therapies, based on evidence of the neurotoxic effects of Aβ, and of the potential adverse effects of brain Aβ burden detected in humans in vivo by positron emission tomography (PET). Progress on passive anti-amyloid immunotherapy research includes ide ntification of antibodies that facilitate microglial activation, catalytical disaggregation, and increased flow of Aβ from cerebrospinal fluid (CSF) to plasma, thus decreasing the neurotoxi...
Source: Neurotherapeutics - July 25, 2023 Category: Neurology Source Type: research
Management Strategies Based on Multi-Modality Neuromonitoring in Severe Traumatic Brain Injury
AbstractSecondary brain injury after neurotrauma is comprised of a host of distinct, potentially concurrent and interacting mechanisms that may exacerbate primary brain insult. Multimodality neuromonitoring is a method of measuring multiple aspects of the brain in order to understand the signatures of these different pathomechanisms and to detect, treat, or prevent potentially reversible secondary brain injuries. The most studied invasive parameters include intracranial pressure (ICP), cerebral perfusion pressure (CPP), autoregulatory indices, brain tissue partial oxygen tension, and tissue energy and metabolism measures s...
Source: Neurotherapeutics - July 25, 2023 Category: Neurology Source Type: research
