Neurotherapeutics最新文献

Paclitaxel (PCX) based treatments, commonly used to treat breast, ovarian and lung cancers, have the highest incidence of chemotherapy-induced neuropathic pain, affecting from 38 to 94 ​% of patients. Unfortunately, analgesic treatments are not always effective for PCX-induced neuropathic pain (PINP). This study aimed to evaluate the antinociceptive effect of clavulanic acid (CLAV), a clinically used β-lactam molecule, in both therapeutic and preventive contexts in mice with PINP. A single dose of CLAV administered after the onset of PINP significantly reduced mechanical hyperalgesia. Interestingly, preventive administration of CLAV prevented PINP development. The effect of preventive CLAV on PINP was associated with increased levels of IL-10 and IFN-β in serum, and decreased levels of IL-1β and TNF-α in both the serum and CNS. Immunostaining experiments revelated that CLAV increased the levels of glutamate transporter type 1 (GLT-1) and toll-like receptor type 4 (TLR4) in the spinal cord, while reducing levels of the astrocytic marker the glial fibrillary acidic protein (GFAP). Notably, co-incubation with CLAV and PCX in triple-negative breast cancer cells did not interfere with PCX-induced cytotoxic effects. Hence, these findings suggest that CLAV could be employed as a clinical treatment aimed at preventing PINP without compromission the cytotoxic efficacy of PCX.

Replacing cells lost during the progression of neurodegenerative disorders holds potential as a therapeutic strategy. Unfortunately, the majority of cells die post-transplantation, which creates logistical and biological challenges for cell therapy approaches. The cause of cell death is likely to be multifactorial in nature but has previously been correlated with hypoxia in the graft core. Here we use mathematical modelling to highlight that grafted cells experiencing hypoxia will also face a rapid decline in glucose availability. Interestingly, three neuron progenitor types derived from stem cell sources, and primary human fetal ventral mesencephalic (VM) cells all remained highly viable in severe hypoxia (0.1 ​% oxygen), countering the idea of rapid hypoxia-induced death in grafts. However, we demonstrate that glucose deprivation, not a paucity of oxygen, was a driver of rapid cell death, which was compounded in ischemic conditions of both oxygen and glucose deprivation. Supplementation of glucose to rat embryonic VM cells transplanted to the adult rat brain failed to improve survival at the dose administered and highlighted the problems of using osmotic minipumps in assisting neural grafting. The data shows that maintaining sufficient glucose in grafts is likely to be of critical importance for cell survival, but better means of achieving sustained glucose delivery is required.

Spinal cord injury (SCI) significantly alters gene expression, potentially impeding functional recovery. This study investigated the effects of atorvastatin, a widely prescribed cholesterol-lowering drug, on gene expression and functional recovery in a chronic murine SCI model. Female C57BL/6J mice underwent moderate 0.25 ​mm lateral compression SCI and received daily atorvastatin (10 ​mg/kg) or vehicle-only injections from two weeks post-injury for four weeks. Sensorimotor functions were assessed using the Basso Mouse Scale (BMS), its subscore, and the inclined plane test. RNA sequencing of spinal cord tissues identified robust transcriptomic changes from SCI and a smaller subset from atorvastatin treatment. Atorvastatin enhanced sensorimotor recovery within two weeks of treatment initiation, with effects persisting to the experimental endpoint. Pathway analysis showed atorvastatin enriched neural regeneration processes including Fatty Acid Transport, Axon Guidance, and the Endocannabinoid Developing Neuron Pathway; improved mitochondrial function via increased TCA Cycle II and reduced Mitochondrial Dysfunction; and decreased Inhibition of Matrix Metalloproteases. Key gene drivers included Fabp7, Unc5c, Rest, and Klf4. Together, these results indicate atorvastatin's potential in chronic SCI recovery, especially where already indicated for cardiovascular protection.

Amyloidogenic protein aggregation is a pathological hallmark of Alzheimer's Disease (AD). As such, this critical feature of the disease has been instrumental in guiding research on the mechanistic basis of disease, diagnostic biomarkers and preventative and therapeutic treatments. Here we review identified molecular triggers and modulators of aggregation for two of the proteins associated with AD: amyloid beta and tau. We aim to provide an overview of how specific molecular factors can impact aggregation kinetics and aggregate structure to promote disease. Looking toward the future, we highlight some research areas of focus that would accelerate efforts to effectively target protein aggregation in AD.

A wide range of acute brain injuries, including both traumatic and non-traumatic causes, can result in elevated intracranial pressure (ICP), which in turn can cause further secondary injury to the brain, initiating a vicious cascade of propagating injury. Elevated ICP is therefore a neurological injury that requires intensive monitoring and time-sensitive interventions. Patients at high risk for developing elevated ICP undergo placement of invasive ICP monitors including external ventricular drains, intraparenchymal ICP monitors, and lumbar drains. These monitors all generate an ICP waveform, but each has its own unique caveats in monitoring and accuracy. Current ICP monitoring and management clinical guidelines focus on the mean ICP derived from the ICP waveform, with standard thresholds of treating ICP greater than 20 ​mmHg or 22 ​mmHg applied broadly to a wide range of patients. However, this one-size fits all approach has been criticized and there is a need to develop personalized, evidence-based and possibly multi-factorial precision-medicine based approaches to the problem. This paper provides historical and physiological context to the problem of elevated ICP, provides an overview of the challenges of the current paradigm of ICP management strategies, and discusses advances in ICP waveform analysis, emerging non-invasive ICP monitoring techniques, and applications of machine learning to create predictive algorithms.

Mitochondrial dysfunction is an important driver of neurodegeneration and synaptic abnormalities in Alzheimer's disease (AD). Amyloid beta (Aβ) in mitochondria leads to increased reactive oxygen species (ROS) production, resulting in a vicious cycle of oxidative stress in coordination with a defective electron transport chain (ETC), decreasing ATP production. AD neurons exhibit impaired mitochondrial dynamics, evidenced by fusion and fission imbalances, increased fragmentation, and deficient mitochondrial biogenesis, contributing to fewer mitochondria in brains of AD patients. Nuclear respiratory factor-1 (NRF1) is a regulator of mitochondrial biogenesis through its activation of mitochondrial transcription factor A (TFAM). Our hypothesis posited that NRF1 induction in neuronal cells exposed to amyloid β_1-42 (Aβ_1-42) would increase de novo mitochondrial synthesis and improve mitochondrial function, restoring neuronal survival. Following NRF1 messenger RNA (mRNA) transfection of Aβ_1-42-treated SH-SY5Y cells, a marked increase in mitochondrial mass was observed. Metabolic programming toward enhanced oxidative phosphorylation resulted in increased ATP production. Oxidative stress in the form of mitochondrial ROS accumulation was reduced and mitochondrial membrane potential preserved. Mitochondrial homeostasis was maintained, evidenced by balanced fusion and fission processes. Ultimately, improvement of mitochondrial function was associated with significant decreases in Aβ_1-42-induced neuronal death and neurite disruption. Our findings highlight the potential of NRF1 upregulation to counteract Aβ_1-42-associated mitochondrial dysfunction and neurodegenerative cell processes, opening avenues for innovative therapeutic approaches aimed at safeguarding mitochondrial health in AD neurons.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide, with limited effective therapeutic options currently available. Recent research has highlighted the pivotal role of mitochondrial dysfunction in the pathophysiology of TBI, making mitochondria an attractive target for therapeutic intervention. This review comprehensively examines advancements in mitochondrial-targeted therapies for TBI, bridging the gap from basic research to clinical applications. We discuss the underlying mechanisms of mitochondrial damage in TBI, including oxidative stress, impaired bioenergetics, mitochondrial dynamics, and apoptotic pathways. Furthermore, we highlight the complex interplay between mitochondrial dysfunction, inflammation, and blood-brain barrier (BBB) integrity, elucidating how these interactions exacerbate injury and impede recovery. We also evaluate various preclinical studies exploring pharmacological agents, gene therapy, and novel drug delivery systems designed to protect and restore mitochondrial function. Clinical trials and their outcomes are assessed to evaluate the translational potential of mitochondrial-targeted therapies in TBI. By integrating findings from bench to bedside, this review emphasizes promising therapeutic avenues and addresses remaining challenges. It also provides guidance for future research to pave the way for innovative treatments that improve patient outcomes in TBI.

Brain ischemia is a major cause of neurological dysfunction and mortality worldwide. It occurs not only acutely, such as in acute ischemic stroke (AIS), but also in chronic conditions like cerebral small vessel disease (cSVD). Any other conditions resulting in brain hypoperfusion can also lead to ischemia. Ischemic events can cause blood-brain barrier (BBB) disruption and, ultimately, white matter alterations, contributing to neurological deficits and long-term functional impairments. Hence, understanding the mechanisms of BBB breakdown and white matter injury across various ischemic conditions is critical for developing effective interventions and improving patient outcomes. This review discusses the proposed mechanisms of ischemia-related BBB breakdown. Moreover, magnetic resonance imaging (MRI) based perfusion-weighted imaging (PWI) techniques sensitive to BBB permeability changes are described, including dynamic contrast-enhanced (DCE-MRI) and dynamic susceptibility contrast MRI (DSC-MRI), two perfusion-weighted imaging (PWI). These PWI techniques provide valuable insights that improve our understanding of the complex early pathophysiology of brain ischemia, which can lead to better assessment and management. Finally, in this review, we explore the implications of the mentioned neuroimaging findings, which emphasize the potential of neuroimaging biomarkers to guide personalized treatment and inform novel neuroprotective strategies. This review highlights the importance of investigating BBB changes in brain ischemia and the critical role of advanced neuroimaging in improving patient care and advancing stroke research.

This article aims to highlight high-quality observational and intervention studies focused on promoting psychological well-being among cardiac arrest (CA) survivors and their families. Following CA, many patients experience significant psychological distress, including depression, generalized anxiety, and post-traumatic stress. Recent studies indicate that this distress can narrow patients' focus, resulting in heightened awareness of cardiac signals-such as fluctuations in heart rate or blood pressure-that lead to constant monitoring and increased anxiety. This anxiety, compounded by behavioral avoidance toward cardioprotective behaviors and physiological hyperarousal, may elevate the risk of secondary cardiovascular diseases and adversely affect the quality of life. Current research is exploring behavioral interventions aimed at reducing this psychological distress, strategies to enhance coping mechanisms, and improving overall health in the survivor-family dyad. Unlike other cardiovascular conditions, no clinical practice guidelines exist for assessing or treating the psychological consequences of CA. Future research should prioritize identifying and treating modifiable psychological factors using targeted therapies and behavioral interventions.

Aneurysmal subarachnoid hemorrhage (aSAH) results in a complex systemic response that is critical to the pathophysiology of late complications and has important effects on outcomes. Omics techniques have expanded our investigational scope and depth into this phenomenon. In particular, metabolomics-the study of small molecules, such as blood products, carbohydrates, amino acids, and lipids-can provide a snapshot of dynamic subcellular processes and thus broaden our understanding of molecular-level pathologic changes that lead to the systemic response after aSAH. Lipids are especially important due to their abundance in the circulating blood and numerous physiological roles. They are comprised of a wide variety of subspecies and are critical for cellular energy metabolism, the integrity of the blood-brain barrier, the formation of cell membranes, and intercellular signaling including neuroinflammation and ferroptosis. In this review, metabolomic and lipidomic pathways associated with aSAH are summarized, centering on key metabolites from each metabolomic domain.