Search Results (27)

Histone deacetylases (HDACs) are key epigenetic regulators that influence chromatin remodeling, gene expression, and cellular plasticity in the central nervous system (CNS). This review provides a comprehensive overview of the classification and functional diversity of HDACs, with particular emphasis on their roles in neural progenitor cells, mature neurons, and glial populations. In neural stem and progenitor cells, HDACs modulate neurogenesis, fate specification, and lineage commitment. In differentiated neurons, HDACs govern synaptic plasticity, memory formation, and survival. In glial cells, including astrocytes and microglia, HDACs orchestrate inflammatory responses, redox balance, and metabolic adaptations. We further examine the dysregulation of HDAC expression and activity in major neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease. Evidence from human post-mortem brain studies reveals region- and isoform-specific alterations in HDAC expression, which are closely associated with cognitive decline, mitochondrial dysfunction, and neuroinflammation. Preclinical studies support the use of HDAC inhibitors (HDACi) as neuroprotective agents, capable of restoring acetylation homeostasis, reducing neuroinflammation, and improving neuronal function. Given the relevance of HDACi, we summarize current clinical studies assessing the safety of these compounds in the context of tumor biology, as well as their potential future applications in neurodegenerative diseases. Together, this review underscores the dual significance of HDACs as biomarkers and therapeutic targets in the context of CNS disorders. Full article

The lithium–pilocarpine rat model of status epilepticus (SE) is a well-established paradigm for studying epileptogenesis. Astrocyte reactivity has been implicated in modulating seizure susceptibility and neuroinflammation, yet its functional role in early epileptogenesis remains unclear. Herein, we evaluated the effects of Mdivi-1, a pharmacological inhibitor of mitochondrial fission protein Drp1, for its ability to modulate astrocytic mitochondrial dynamics and for its reported preventive neuroprotective properties. Mdivi-1 was administered shortly after SE onset, and we assessed brain glucose metabolism using [¹⁸F]FDG PET, alongside histological markers of neurodegeneration, astrocyte reactivity, and microglial activation, at 3 days post-SE. As expected, SE induced widespread brain hypometabolism measured by a VOI analysis, hippocampal neurodegeneration, and glial activation. Post-SE Mdivi-1 administration reduced hippocampal astrogliosis but neither conferred neuroprotection nor rescued glucose metabolism. On the contrary, Mdivi-1 exacerbated limbic–cortical hypometabolism when evaluated by SPM and normalized to whole brain tracer uptake and microglia-mediated neuroinflammation. These findings challenge the assumption that early astrocyte inhibition confers neuroprotection. Furthermore, early suppression of astrocyte reactivity after the damage has occurred may shift the neuroinflammatory response toward maladaptive microglial activation. Thus, while Mdivi-1 holds promise as a preventive neuroprotective agent, its use post-SE may have unintended adverse effects on the brain’s response to SE. Full article

Valproic acid (VPA) is a widely prescribed antiepileptic agent whose teratogenic potential has been recognized. In recent years, VPA has been shown to promote neuronal regeneration; however, the exact molecular mechanisms are not fully understood. This study elucidates the pH-dependent pathway through which VPA promotes the differentiation of satellite glial cells (SGCs) into neurons. We observed sustained intracellular pH elevation during the VPA-induced neural differentiation of SGCs, and the modulation of intracellular pH was shown to influence this differentiation process. Then, we found that VPA regulates intracellular pH through NHE1 (sodium–hydrogen exchanger 1), and that the pharmacological inhibition of NHE1 not only attenuated intracellular pH elevation but also substantially impaired VPA-induced neuronal differentiation. Finally, our results showed that the elevated intracellular pH promoted the neuronal differentiation of SGCs by activating β-catenin signaling. These findings provide novel insights into the mechanisms of VPA-induced neurogenesis, advancing our understanding of its pharmacological profile and informing its potential therapeutic application in neuronal regeneration strategies. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by amyloid-β plaque accumulation, tau tangles, and extensive neuroinflammation. Neuroinflammation, driven by glial cells like microglia and astrocytes, plays a critical role in AD progression. Initially, these cells provide protective functions, such as debris clearance and neurotrophic support. However, as AD progresses, chronic activation of these cells exacerbates inflammation, contributing to synaptic dysfunction, neuronal loss, and cognitive decline. Microglia release pro-inflammatory cytokines and reactive oxygen species (ROS), while astrocytes undergo reactive astrogliosis, further impairing neuronal health. This maladaptive response from glial cells significantly accelerates disease pathology. Current AD treatments primarily aim at symptomatic relief, with limited success in disease modification. While amyloid-targeting therapies like Aducanumab and Lecanemab show some promise, their efficacy remains limited. In this context, natural compounds have gained attention for their potential to modulate neuroinflammation and promote neuroprotection. Among these, butyrate and lauric acid are particularly notable. Butyrate, produced by a healthy gut microbiome, acts as a histone deacetylase (HDAC) inhibitor, reducing pro-inflammatory cytokines and supporting neuronal health. Lauric acid, on the other hand, enhances mitochondrial function, reduces oxidative stress, and modulates inflammatory pathways, thereby supporting glial and neuronal health. Both compounds have been shown to decrease amyloid-β deposition, reduce neuroinflammation, and promote neuroprotection in AD models. This review explores the mechanisms through which butyrate and lauric acid modulate glial and neuronal activity, highlighting their potential as therapeutic agents for mitigating neuroinflammation and slowing AD progression. Full article

Neuroinflammatory responses are central to the pathogenesis of neurodegenerative diseases, affecting cells of both neuronal and glial origin that respond to immune-driven inflammatory stimuli. The PI3K/mTOR signaling pathway is essential for the regulation of these neuroinflammatory processes and is therefore a promising target for therapeutic intervention. Here, we investigated the consequences of PI3K/mTOR pathway inhibition on neuroinflammation employing PF-04691502, an agent with combined PI3K and mTOR inhibitory activity. We treated SH-SY5Y, C6, BV-2, and Mo3.13 cell lines with PF-04691502 at concentrations of 0.1, 0.5, and 1 µM to assess the modulation of neuroinflammatory responses. To induce inflammation, cells were stimulated with lipopolysaccharide (LPS, 1 μg/mL) and interferon-gamma (IFN-γ, 100 U/mL). The results from the MTT assays demonstrated that PI3K/mTOR inhibition preserved cell viability at 0.5 and 1 µM across all of the cell lines, indicating its potential to mitigate inflammation-driven cytotoxicity. Subsequent ELISA assays revealed a marked decrease in the NF-κB and pro-inflammatory cytokine levels, confirming the effective suppression of inflammation through PI3K/mTOR inhibition. In addition, the SH-SY5Y cell line was exposed to MPP+ to simulate Parkinson’s disease (PD)-like toxicity; then, cell viability, PD-associated markers, and apoptotic indicators were assessed. Our results indicate that inhibition of the PI3K/mTOR signaling axis may alleviate neurodegenerative processes by modulating both neuroinflammatory responses and apoptotic pathways. These findings highlight the therapeutic promise of targeting PI3K/mTOR in the context of neurodegenerative disorders and support the need for further validation through in vivo and clinical investigations. Full article

Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder that significantly impacts learning, daily functioning, and personal development. Astaxanthin (ASTA), a naturally occurring antioxidant, has garnered interest as a potential therapeutic agent for various diseases, particularly in mitigating oxidative stress. This study explores a novel application of ASTA in the context of ADHD, aiming to investigate its therapeutic effects and underlying mechanisms. Spontaneously hypertensive rats (SHRs), widely used ADHD model animals, were treated with ASTA (50/100 mg/kg/day) for three weeks, 5 mg/kg/day atomoxetine (ATO) as the positive, and Wistar Kyoto (WKY) rats as control. Behavioral improvements were assessed using the open field test (OFT) and the Morris water maze (MWM). Biochemical analyses were conducted to evaluate changes in the levels of various neurotrophic factors, while histological examinations were performed to assess neuroprotective effects. Additionally, the role of ASTA in the brain–gut axis was investigated. The behavioral symptoms of hyperactivity, anxiety, and impaired spatial memory in ADHD animals were mitigated by ASTA. This improvement is primarily attributed to the restoration of neurotransmitter levels, particularly dopamine (DA), achieved through the modulation of several critical components within the dopamine system, including dopamine receptor 1 (DR1), dopamine transporter (DAT), tyrosine hydroxylase (TH), and synaptic-associated protein 25 (SNAP-25). Additionally, regulating the serotonin transporter (SERT) and glial cell-derived neurotrophic factor (GDNF) supports the recovery of serotonin levels and facilitates optimal brain development. Furthermore, cerebellar cells were protected, and the structure of the intestinal microbiota was regulated. ASTA can mitigate ADHD symptoms in SHR through the modulation of the dopaminergic system, multiple neurotransmitters, neurotrophic factors, and the neuro-intestinal environment, which establishes ASTA as a promising nutraceutical candidate for adjunctive therapy in pediatric ADHD. Full article

Innovations in spinal cord injury (SCI) models are crucial for developing effective therapies. This study introduces a novel in vitro SCI model using cultures of primary mixed spinal cord cells from rat pups, featuring key spinal cord cell types. This model offers distinct advantages in terms of feasibility, reproducibility, and cost-effectiveness, requiring only basic cell culture equipment. Following hyperosmotic stress via sorbitol treatment, the model recapitulated SCI pathophysiological hallmarks, with a 65% reduction in cell viability and gradual cell death over 48 h, making it ideal for evaluating neuroprotective agents. Notably, the human adipose tissue stem cell (hASC) secretome provided significant protection: it preserved metabolic viability, reduced β amyloid precursor protein (β-APP) expression in surviving neurons, and modulated the shift in the astrocytic morphotype. A transcriptomic profile of the effect of the hASC secretome treatment showed significant functional enrichments related to cell proliferation and cycle progression pathways. In addition to supporting the use of the hASC secretome as a therapy for SCI, this study is the first to use sorbitol as a hyperosmolar stressor to recapitulate key aspects of SCI pathophysiology. Thereby, this model can be used as a promising platform for evaluating therapeutic agents targeting neuroprotection and neuroregeneration, offering outputs related to cell death, neuronal stress, and protection, as well as induction of glial reactivity. Full article

Neuroinflammation is a complex immune response triggered by brain injury or pathological stimuli, and is highly exacerbated in neurodegenerative diseases. It plays a dual role in the central nervous system, promoting repair in acute stages while aggravating disease progression by contributing to neuronal loss, synaptic dysfunction, and glial dysregulation in chronic phases. Inflammatory responses are mainly orchestrated by microglia and infiltrated monocytes, which, when dysregulated, not only harm existing neurons, but also impair the survival and differentiation of neural stem and progenitor cells in the affected brain regions. Modulating neuroinflammation is crucial for harnessing its protective functions while minimizing its detrimental effects. Current therapeutic strategies focus on fine-tuning inflammatory responses through pharmacological agents, bioactive molecules, and stem cell-based therapies. These approaches aim to restore immune homeostasis, support neuroprotection, and promote regeneration in various neurological disorders. However, animal models sometimes fail to reproduce human-specific inflammatory responses in the brain. In this context, stem-cell-derived models provide a powerful tool to study neuroinflammatory mechanisms in a patient-specific and physiologically relevant context. These models facilitate high-throughput screening, personalized medicine, and the development of targeted therapies while addressing the limitations of traditional animal models, paving the way for more targeted and effective treatments. Full article

In recent decades, substantial evidence has highlighted the integral roles of neuroglia, particularly astrocytes, microglia, oligodendrocytes, and ependymal cells, in the regulation of synaptic transmission, metabolic support, and immune mechanisms within the central nervous system. In addition to their structural role, these cells actively modulate neurotransmitter homeostasis and influence neuronal plasticity, thereby affecting cognition, mood, and behavior. This review discusses how neuroglial alterations contribute to the pathophysiology of five common psychiatric disorders: major depression, bipolar disorder, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and schizophrenia. We synthesized preclinical and clinical findings illustrating that glial dysfunction, including impaired myelination and aberrant neuroinflammatory responses, often parallels disease onset and severity. Moreover, we outline how disruptions in astrocytic glutamate uptake, microglia-mediated synaptic pruning, and blood–brain barrier integrity may underlie the neurobiological heterogeneity observed in these disorders. The therapeutic implications range from anti-inflammatory agents to investigational compounds that aim to stabilize glial function or promote remyelination. However, challenges due to interindividual variability, insufficient biomarkers, and the multifactorial nature of psychiatric illnesses remain. Advances in neuroimaging, liquid biopsy, and more precise molecular techniques may facilitate targeted interventions by stratifying patient subgroups with distinct glial phenotypes. Continued research is essential to translate these insights into clinically efficacious and safe treatments. Full article

The complexity of Alzheimer’s disease (AD) pathophysiology represents a significant challenge in the development of effective therapeutic agents for its treatment. CNEURO-201 (CN, also Amylovis-201) is a novel pharmaceutical agent with dual activity as an anti-amyloid-β (Aβ) agent and σ1 receptor agonist. CN exhibits great efficacy at very low doses, delaying cognitive impairment and alleviating Aβ load in animal models of AD. However, CN functions on other remains related to this pathology remain to be investigated. The present study sought to evaluate the effects of CN treatment at a dosage of 0.1 mg kg⁻¹ (p.o) over an eight-week period in the 3xTg-AD mouse model. In silico studies, as well as biochemical and immunofluorescence assays, were conducted on brain tissue to investigate the CN effects on acetylcholine metabolism, redox system, and glial cell activation-related biomarkers in brain regions that are relevant for memory. The results demonstrated that CN effectively rescues cognitive impairment of 3xTg-AD mice by influencing glial activity to reduce existing Aβ plaques but also modulating acetylcholine metabolism and the enzymatic response of proteins involved in the redox system. Our outcomes reinforced the potential of CN in treating AD by acting on multiple pathways altered in this disease. Full article

Background/Objectives: Complex regional pain syndrome (CRPS) is characterized by severe pain and reduced functionality, which can significantly affect an individual’s quality of life. The current treatment of CRPS is challenging. However, recent advances in diagnostic and treatment methods show promise for improving patient outcomes. This review aims to place the question of CRPS in a broader context and highlight the objectives of the research for future directions in the management of CRPS. Methods: This study involved a comprehensive literature review. Results: Research has identified three primary pathophysiological pathways that may explain the clinical variability observed in CRPS: inflammatory mechanisms, vasomotor dysfunction, and maladaptive neuroplasticity. Investigations into these pathways have spurred the development of novel diagnostic and treatment strategies focused on N-Methyl-D-aspartate Receptor Antagonists (NMDA), Toll-like receptor 4 (TLR-4), α1 and α2 adrenoreceptors, as well as the identification of microRNA (miRNA) biomarkers. Treatment methods being explored include immune and glial-modulating agents, intravenous immunoglobulin (IVIG) therapy, plasma exchange therapy, and neuromodulation techniques. Additionally, there is ongoing debate regarding the efficacy of other treatments, such as free radical scavengers, alpha-lipoic acid (ALA), dimethyl fumarate (DMF), adenosine monophosphate-activated protein kinase (AMPK) activators such as metformin, and phosphodiesterase-5 inhibitors such as tadalafil. Conclusions: The controversies surrounding the mechanisms, diagnosis, and treatment of CRPS have prompted researchers to investigate new approaches aimed at enhancing understanding and management of the condition, with the goal of alleviating symptoms and reducing associated disabilities. Full article

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen–alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial-cell-line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases. This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium-iodate (SI)-induced retinal degeneration. The findings indicated that the CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants. Full article

A traumatic brain injury (TBI) is a major health issue affecting many people across the world, causing significant morbidity and mortality. TBIs often have long-lasting effects, disrupting daily life and functionality. They cause two types of damage to the brain: primary and secondary. Secondary damage is particularly critical as it involves complex processes unfolding after the initial injury. These processes can lead to cell damage and death in the brain. Understanding how these processes damage the brain is crucial for finding new treatments. This review examines a wide range of literature from 2021 to 2023, focusing on biomarkers and molecular mechanisms in TBIs to pinpoint therapeutic advancements. Baseline levels of biomarkers, including neurofilament light chain (NF-L), ubiquitin carboxy-terminal hydrolase-L1 (UCH-L1), Tau, and glial fibrillary acidic protein (GFAP) in TBI, have demonstrated prognostic value for cognitive outcomes, laying the groundwork for personalized treatment strategies. In terms of pharmacological progress, the most promising approaches currently target neuroinflammation, oxidative stress, and apoptotic mechanisms. Agents that can modulate these pathways offer the potential to reduce a TBI’s impact and aid in neurological rehabilitation. Future research is poised to refine these therapeutic approaches, potentially revolutionizing TBI treatment. Full article

Alzheimer’s disease (AD), marked by cognitive impairment, predominantly affects the brain regions regulated by cholinergic innervation, such as the cerebral cortex and hippocampus. Cholinergic dysfunction, a key contributor to age-related cognitive decline, has spurred investigations into potential therapeutic interventions. We have previously shown that choline alphoscerate (α-GPC), a cholinergic neurotransmission-enhancing agent, protects from Aβ-mediated neurotoxicity. Herein, we investigated the effects of α-GPC on the microglial phenotype in response to Aβ via modulation of the nicotinic alpha-7 acetylcholine receptor (α7 nAChR). BV2 microglial cells were pre-treated for 1 h with α-GPC and were treated for 24, 48, and 72 h with Aβ_1–42 and/or α-BTX, a selective α7nAchR antagonist. Fluorescent immunocytochemistry and Western blot analysis showed that α-GPC was able to antagonize Aβ-induced inflammatory effects. Of note, α-GPC exerted its anti-inflammatory effect by directly activating the α7nAChR receptor, as suggested by the induction of an increase in [Ca²⁺]_i and Ach-like currents. Considering that cholinergic transmission appears crucial in regulating the inflammatory profiles of glial cells, its modulation emerges as a potential pharmaco-therapeutic target to improve outcomes in inflammatory neurodegenerative disorders, such as AD. Full article

Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose. Administration of Cris-104 and donepezil combination (3 μmol/kg) successfully reversed hyperalgesia and mechanical allodynia observed in rats subjected to spinal nerve ligation (SNL). The combination also modulated neuroinflammation by reducing astrocyte activation, evident in the decreased expression of glial fibrillary acidic protein (GFAP) in the spinal cord. The observed synergism in combining a nicotinic receptor agonist with an anticholinesterase agent underscores its potential for treating chronic pain. This alternative therapeutic distinct advantage, including dose reduction and high selectivity for the receptor, contribute to a more favorable profile with minimized adverse effects. Full article