Neurotherapeutics最新文献

Chemotherapy-induced peripheral neuropathy (CIPN) and its related pain are common challenges for patients receiving oxaliplatin chemotherapy. Oxaliplatin accumulation in dorsal root ganglion (DRGs) is known to impair gene transcription by epigenetic dysregulation. We hypothesized that sodium butyrate, a pro-resolution short-chain fatty acid, inhibited histone acetylation in DRGs and abolished K⁺ channel dysregulation-induced neuronal hyperexcitability after oxaliplatin treatment. Mechanical allodynia and cold hyperalgesia of mice receiving an accumulation of 15 ​mg/kg oxaliplatin, with or without intraperitoneal sodium butyrate supplementation, were assessed using von Frey test and acetone evaporation test. Differential expressions of histone deacetylases (HDACs) and pain-related K⁺ channels were quantified with rt-qPCR and protein assays. Immunofluorescence assays of histone acetylation at H3K9/14 were performed in primary DRG cultures treated with sodium butyrate. Current clamp recording of action potentials and persistent outward current of Twik-related-spinal cord K⁺ (TRESK) channel were recorded in DRG neurons with small diameters extract. Accompanied by mechanical allodynia and cold hyperalgesia, HDAC1 was upregulated in mice receiving oxaliplatin treatment. Sodium butyrate enhanced global histone acetylation at H3K9/14 in DRG neurons. In vivo sodium butyrate supplementation restored oxaliplatin-induced Kcnj9 and Kcnk18 expression and pain-related behaviors in mice for at least 14 days. Oxaliplatin-induced increase in action potentials frequencies and decrease in magnitudes of KCNK18-related current were reversed in mice receiving sodium butyrate supplementation. This study suggests that sodium butyrate was a useful agent to relieve oxaliplatin-mediated neuropathic pain.

Little is known about the mechanisms that generate epileptic spasms following perinatal brain injury. Recent studies have implicated reduced levels of Insulin-like Growth Factor 1 (IGF-1) in these patients' brains. Other studies have reported low levels of the inhibitory neurotransmitter, GABA. In the TTX brain injury model of epileptic spasms, we undertook experiments to evaluate the impact of IGF-1 deficiencies on neocortical interneurons and their role in spasms. Quantitative immunohistochemical analyses revealed that neocortical interneurons that express glutamic acid decarboxylase, parvalbumin, or synaptotagmin 2 co-express IGF-1. In epileptic rats, expression of these three interneuron markers were reduced in the neocortex. IGF-1 expression was also reduced, but surprisingly this loss was confined to interneurons. Interneuron connectivity was reduced in tandem with IGF-1 deficiencies. Similar changes were observed in surgically resected neocortex from infantile epileptic spasms syndrome (IESS) patients. To evaluate the impact of IGF-1 deficiencies on interneuron development, IGF-1R levels were reduced in the neocortex of neonatal conditional IGF-1R knock out mice by viral injections. Four weeks later, this experimental maneuver resulted in similar reductions in interneuron connectivity. Treatment with the IGF-1 derived tripeptide, (1-3)IGF-1, abolished epileptic spasms in most animals, rescued interneuron connectivity, and restored neocortical levels of IGF-1. Our results implicate interneuron IGF-1 deficiencies, possibly impaired autocrine IGF-1 signaling and a resultant interneuron dysmaturation in epileptic spasm generation. By restoring IGF-1 levels, (1-3)IGF-1 likely suppresses spasms by rescuing interneuron connectivity. Results point to (1-3)IGF-1 and its analogues as potential novel disease-modifying therapies for this neurodevelopmental disorder.

Innate immunity protein interferon induced transmembrane protein 3 (IFITM3) is a transmembrane protein that has a wide array of functions, including in viral infections, Alzheimer's Disease (AD), and cancer. As an interferon stimulated gene (ISG), IFITM3's expression is upregulated by type-I, II, and III interferons. Moreover, the antiviral activity of IFITM3 is modulated by post-translational modifications. IFITM3 functions in innate immunity to disrupt viral fusion and entry to the plasma membrane as well as prevent viral escape from endosomes. As a γ-secretase modulatory protein, IFITM3 distinctly modulates the processing of amyloid precursor protein (APP) to generate amyloid beta peptides (Aβ) and Notch1 cleavages. Increased IFITM3 expression, which can result from aging, cytokine activation, inflammation, and infection, can lead to an upregulation of γ-secretase for Aβ production that causes a risk of AD. Therefore, the prevention of IFITM3 upregulation has potential in the development of novel therapies for the treatment of AD.

Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 ​% lower (P ​= ​0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 ​% lower DNM1 levels than those without impairment (P ​= ​0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 ​% decline (P ​< ​0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P ​< ​0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.

The angioedema risk may vary among stroke patients receiving different thrombolytic agents. This study aimed to investigate the angioedema risk associated with different thrombolytic agents and to identify associated risk factors. We conducted a large-scale retrospective pharmacovigilance study using the FDA Adverse Event Reporting System (FAERS) database. Stroke patients receiving thrombolytic therapy (i.e., alteplase or tenecteplase) were identified, and the associations with angioedema were explored using disproportionality analysis and time-to-onset analysis. Additionally, we used adapted Bradford Hill criteria to confirm these associations. Risk factors for angioedema were explored using stepwise logistic regression. A total of 17,776 stroke patients were included, with 2973 receiving alteplase and 278 receiving tenecteplase. Disproportionality analysis revealed that angioedema might be associated with alteplase (adjusted ROR [aROR] 5.13 [95 ​% CI, 4.55-5.79]) or tenecteplase (aROR 2.72 [95 ​% CI, 1.98-3.67]). The adapted Bradford Hill criteria suggested a probable causal relationship between alteplase and angioedema, whereas there was insufficient evidence of a probable causal relationship with tenecteplase. Multivariate analysis revealed that ACE-inhibitors use (aROR 9.73 [95 ​% CI, 7.29-12.98]), female sex (aROR 1.38 [95 ​% CI, 1.13-1.67]) and hypertension (aROR 2.11 [95 ​% CI, 1.52-2.92]) were significant risk factors for angioedema among alteplase-treated stroke patients. Our study suggested that alteplase is associated with a greater risk of angioedema among stroke patients, but there is insufficient evidence to support an association between tenecteplase and angioedema. Clinicians should be vigilant for this potentially life-threatening complication, particularly in patients with identified risk factors. It is also prudent to consider tenecteplase as an alternative, if available.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, not least in the elderly. The incidence of aged TBI patients has increased dramatically during the last decades. High age is a highly negative prognostic factor in TBI, and pharmacological treatment options are lacking. We used the controlled cortical impact (CCI) TBI model in 23-month-old male and female mice and analyzed the effect of post-injury treatment with 7,8 dihydroxyflavone (7,8-DHF), a brain-derived neurotrophic factor (BDNF)-mimetic compound, on white matter pathology. Following CCI or sham injury, mice received subcutaneous 7,8-DHF injections (5 ​mg/kg) 30 ​min post-injury and were sacrificed on 2, 7 or 14 days post-injury (dpi) for histological and immunofluorescence analyses. Histological assessment with Luxol Fast Blue (LFB)/Cresyl Violet stain showed that administration of 7,8-DHF resulted in preserved white matter tissue at 2 and 7 dpi with no difference in cortical tissue loss at all investigated time points. Treatment with 7,8-DHF led to reduced axonal swellings at 2 and 7 dpi, as visualized by SMI-31 (Neurofilament Heavy Chain) immunofluorescence, and reduced number of TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labelling)/CC1-positive mature oligodendrocytes at 2 dpi in the perilesional white matter. Post-injury proliferation of Platelet-derived Growth Factor Receptor (PDGFRα)-positive oligodendodrocyte progenitor cells was not altered by 7,8-DHF. Our results suggest that 7,8-DHF can attenuate white matter pathology by mitigating axonal injury and oligodendrocyte death in the aged mouse brain following TBI. These data argue that further exploration of 7,8-DHF towards clinical use is warranted.

Mirodenafil is a phosphodiesterase 5 (PDE5) inhibitor with high specificity for its target and good blood-brain barrier permeability. The drug, which is currently used for treatment of erectile dysfunction, reduces Aβ and pTau levels and improves cognitive function in mouse models of Alzheimer's disease. In the present study, we investigated the effect of mirodenafil in the transient and permanent middle cerebral artery occlusion (tMCAO and pMCAO) models of stroke in rats. Starting 24 ​h after cerebral artery occlusion, mirodenafil was administered subcutaneously at doses of 0.5, 1, and 2 ​mg/kg per day for 9 days in the tMCAO model and for 28 days in the pMCAO model. Mirodenafil significantly increased sensorimotor and cognitive recovery of tMCAO and pMCAO rats compared to saline control rats, and significantly decreased the amount of degenerative cells and cleaved caspase-3 and cleaved PARP immunoreactive cells. Effects were seen in a dose-dependent manner up to 1 ​mg/kg mirodenafil. The benefits of mirodenafil treatment increased with longer treatment duration, and the largest improvements over control were typically observed on the last assessment day. There was no effect of mirodenafil on infarct volume in both tMCAO and pMCAO rats. In an experiment to determine the treatment window for mirodenafil effects, a protective effect was observed when treatment was delayed 72 ​h after MCAO, although the most improvement was observed with shorter treatment windows. Using pMCAO and tMCAO rat models of stroke, we determined that mirodenafil improves the recovery of sensorimotor and cognitive functions after MCAO and protects cortical cells from apoptosis and degeneration. Greater benefit was observed with longer duration of treatment, and improvement was seen even when treatment was delayed.

Since the discovery and characterization of the PD-1/PD-L pathway, mounting evidence has emerged regarding its role in regulating neuroinflammation following cerebrovascular injury. Classically, PD-L1 on antigen-presenting cells or tissues binds PD-1 on T cell surfaces resulting in T cell inhibition. In myeloid cells, PD-1 stimulation induces polarization of microglia and macrophages into an anti-inflammatory, restorative phenotype. The therapeutic potential of PD-1 agonism in ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage-related vasospasm, and traumatic brain injury rests on the notion of harnessing the immunomodulatory function of immune checkpoint pathways to temper the harmful effects of immune overactivation and secondary injury while promoting repair and recovery. Immune checkpoint agonism has greater specificity than the wider and non-specific anti-inflammatory effects of other agents, such as steroids. PD-1 agonism has already demonstrated success in clinical trials for rheumatoid arthritis and is being tested in other chronic inflammatory diseases. Further investigation of PD-1 agonism as a therapeutic strategy in cerebrovascular injury can help clarify the mechanisms underlying clinical benefit, develop drugs with optimal pharmacodynamic and pharmacokinetic properties, and mitigate unwanted side effects.