Neuronal Survival Research Articles

Investigating the Interplay Between the Nrf2/Keap1/HO-1/SIRT-1 Pathway and the p75NTR/PI3K/Akt/MAPK Cascade in Neurological Disorders: Mechanistic Insights and Therapeutic Innovations.

Neurological illnesses are debilitating diseases that affect brain function and balance. Due to their complicated aetiologies and progressive nature, neurodegenerative and neuropsychiatric illnesses are difficult to treat. These incurable conditions damage brain functions like mobility, cognition, and emotional regulation, but medication, gene therapy, and physical therapy can manage symptoms. Disruptions in cellular signalling pathways, especially those involving oxidative stress response, memory processing, and neurotransmitter modulation, contribute to these illnesses. This review stresses the interplay between key signalling pathways involved in neurological diseases, such as the Nrf2/Keap1/HO-1/SIRT-1 axis and the p75NTR/PI3K/Akt/MAPK cascade. To protect neurons from oxidative damage and death, the Nrf2 transcription factor promotes antioxidant enzyme production. The Keap1 protein releases Nrf2 during oxidative stress for nuclear translocation and gene activation. The review also discusses how neurotrophin signalling through the p75 neurotrophin receptor (p75NTR) determines cell destiny, whether pro-survival or apoptotic. The article highlights emerging treatment approaches targeting these signalling pathways by mapping these connections. Continued research into these molecular pathways may lead to new neurological disease treatments that restore cellular function and neuronal survival. In addition to enhanced delivery technologies, specific modulators and combination therapies should be developed to fine-tune signalling responses. Understanding these crosstalk dynamics is crucial to strengthening neurological illness treatment options and quality of life.

Regional Alterations in Müller Cell Protein Expression in Human and a Rat Model of Geographic Atrophy.

Despite being crucial to neuronal survival, the role Müller cells play in geographic atrophy (GA) has only recently been considered. We investigated whether Müller cells retain their normal functional profile or form a fibrotic scar when remodeling in human GA eyes and our subretinal sodium iodate (NaIO3) model. Sprague Dawley rats given subretinal injections of NaIO3 (5 mg/mL) were sacrificed at 3 and 12 weeks. Cryosections and retinal flatmounts from rats and cryosections from human GA eyes were stained with antibodies against the Müller cell proteins glutamine synthetase (GS), inwardly rectifying potassium channel 4.1 (Kir4.1), aquaporin 4 (AQP4), cellular retinaldehyde-binding protein 1 (CRALBP), and glial fibrillary acidic protein (GFAP), as well as alpha smooth muscle actin (α-SMA), fibronectin, and collagens I and IV. The immunofluorescence intensity of AQP4 and Kir4.1 was quantified using Image J, and Kir4.1 protein levels were verified by western blot. In both human GA eyes and NaIO3-injected rats, Müller cell processes at the external limiting membrane (ELM) descent and in the subretinal membrane exhibited increased GS expression. GFAP was elevated throughout the Müller cells. AQP4 staining at the ELM descent was particularly pronounced throughout the radial processes, including those extending into the subretinal space. In NaIO3-injected rats, perivascular Kir4.1 expression significantly decreased in the atrophic retina, but expression increased in the subretinal glial membrane. α-SMA and extracellular matrix proteins were not detected in the subretinal membrane. Our findings underscore the persistence of homeostatic proteins, albeit altered, in Müller cells as they remodel and extend into the subretinal space.

Graphene Quantum Dots Attenuate TDP-43 Proteinopathy in Amyotrophic Lateral Sclerosis.

Aberrant phase separation- and stress granule (SG)-mediated cytosolic aggregation of TDP-43 in motor neurons is the hallmark of amyotrophic lateral sclerosis (ALS). In this study, we found that graphene quantum dots (GQDs) potentially modulate TDP-43 aggregation during SG dynamics and phase separation. The intrinsically disordered region in the C-terminus of TDP-43 exhibited amyloid fibril formation; however, GQDs inhibited the formation of amyloid fibrils through direct intermolecular interactions with TDP-43. These effects were accompanied by attenuation of the ALS phenotype in animal models. Additionally, GQDs delayed the onset and survival of TDP-43 transgenic mouse models by enhancing motor neuron survival, reducing glial activation, and reducing the cytosolic aggregation of TDP-43 in motor neurons. In this research, we demonstrated the efficacy of GQDs on the SG-mediated aggregation of TDP-43 and the binding property of GQDs with TDP-43. Additionally, we demonstrated the clinical feasibility of GQDs using several animal models and other types of ALS caused by FUS and C9orf72. Therefore, GQDs could offer a new therapeutic approach for proteinopathy-associated ALS.

Evidence from a mouse model supports repurposing an anti-asthmatic drug, bambuterol, against Alzheimer's disease by administration through an intranasal route.

Bambuterol is a long-acting anti-asthmatic prodrug which releases terbutaline. Terbutaline is an agonist of the β2-adrenergic receptors which is formed by decarbamoylation of bambuterol by butyrylcholinesterase. Inhibition of the latter, as well as activation of β2-AR, are of interest for the treatment of Alzheimer's disease (AD). Combining these two activities, bambuterol could express a good clinical efficacy against AD. The present work firstly confirmed the capacity of bambuterol to display in celluloneuroprotective activities, reduction of Tau hyperphosphorylation and preservation of synapses in rat hippocampal neuronal cultures intoxicated with Aβ peptides. Further, bambuterol, in the form of a liposomal gel, showed a good bioavailability in CNS after intranasal administration, which should reduce any side effects linked to peripheral terbutaline release. Indeed, even if the latter is more selective than other β2-mimetics towards bronchial β2-AR, cardiovascular effects (tachycardia, arrhythmias…) could occur upon cardiac β1-AR activation. Finally, intranasal administration of low doses of bambuterol gel in mice intoxicated with Aβ peptides, prevented long-term spatial memory impairment and showed beneficial effects on the survival of neurons and on synapse preservation.

Edaravone Mitigates Hippocampal Neuronal Death and Cognitive Dysfunction by Upregulating BDNF Expression in Neonatal Hypoxic-Ischemic Rats.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a severe neurological injury during infancy, often resulting in long-term cognitive deficits. This study aimed to investigate the neuroprotective effects of Edaravone (EDA), a free radical scavenger, and elucidate the potential role of brain-derived neurotrophic factor (BDNF) in mediating these effects in neonatal HIE rats. Using the Rice-Vannucci model, HIE was induced in neonatal rats, followed by immediate administration of EDA after the hypoxic-ischemic insult. To examine the role of BDNF, a separate group of rats received intrahippocampal injections of a lentiviral vector for BDNF knockdown prior to the induction of HIE and subsequent EDA treatment. Neuronal survival and apoptosis in the hippocampal region were assessed by immunofluorescence and TUNEL staining, respectively. BDNF expression levels in the hippocampus were analysed using enzyme-linked immunosorbent assay (ELISA). Cognitive function was evaluated using the Morris water maze (MWM) and Y maze tests. Results demonstrated that EDA significantly reduced hippocampal neuronal apoptosis and death, increased neuronal survival, and enhanced BDNF expression compared to the control group. However, the therapeutic effects of EDA were mitigated in the BDNF knockdown group, indicating a crucial role of BDNF in mediating the neuroprotective effects of EDA. Behavioural testing confirmed that EDA treatment significantly improved spatial learning and memory abilities in HIE rats, but these improvements were not observed in rats with BDNF knockdown. In conclusion, our study suggests that EDA treatment mitigates hippocampal neuronal death and improves cognitive dysfunction in HIE rats primarily by upregulating BDNF expression. These findings provide experimental support for the potential application of EDA in the treatment of HIE and highlight the essential role of BDNF in neuroprotection and cognitive recovery post-HIE.

Amyloid-β can activate JNK signalling via WNT5A-ROR2 to reduce synapse formation in Alzheimer's disease.

Wnt signalling is an essential signalling system in neurogenesis, with a crucial role in synaptic plasticity and neuronal survival, processes that are disrupted in Alzheimer's disease (AD). Within this network, the Wnt/β-catenin pathway has been studied for its neuroprotective role, and this is suppressed in AD. However, the involvement of the non-canonical Wnt-planar cell polarity (Wnt/PCP) pathway in AD remains to be determined. This study investigates the role of ROR2, a Wnt/PCP co-receptor, in synaptogenesis. We demonstrate that WNT5A-ROR2 signalling activates the JNK pathway, leading to synapse loss in mature neurons. This effect mirrors the synaptotoxic actions of Aβ1-42 and DKK1, which are elevated in AD. Notably, blocking ROR2 and JNK mitigates Aβ1-42 and DKK1-induced synapse loss, suggesting their dependence on ROR2. In induced pluripotent stem cell (iPSC)-derived cortical neurons carrying a PSEN1 mutation, known to increase the Aβ42/40 ratio, we observed increased WNT5A-ROR2 clustering and reduced numbers of synapses. Inhibiting ROR2 or JNK partially rescued synaptogenesis in these neurons. These findings suggest that, unlike the Wnt/β-catenin pathway, the Wnt/PCP-ROR2 signalling pathway can operate in a feedback loop with Aβ1-42 to enhance JNK signalling and contribute to synapse loss in AD.

The role of CXCL12/CXCR4/CXCR7 axis in cognitive impairment associated with neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Multiple Sclerosis (MS), and Amyotrophic Lateral Sclerosis (ALS), are characterized by progressive neuronal loss and cognitive impairment (CI). The: Cysteine-X-cysteine chemokine ligand 12(CXCL12)/CXC chemokine receptor type 4 (CXCR4)/CXC chemokine receptor type 7 (CXCR7) axis has emerged as a critical molecular pathway in the development of CI in these disorders. This review explores the role of this axis in the pathogenesis of CI across these neurodegenerative diseases, synthesizing current evidence and its implications for targeted therapies. In AD, dysregulation of this axis contributes to amyloid-β accumulation and tau hyperphosphorylation, leading to synaptic dysfunction and cognitive decline. PD studies reveal that CXCL12/CXCR4 signaling influences dopaminergic neuron survival and microglial activation, affecting cognitive function. In MS, the axis modulates neuroinflammation and demyelination processes, impacting cognitive performance. ALS research indicates that the CXCL12/CXCR4/CXCR7 pathway is involved in motor neuron degeneration and associated cognitive deficits. Across these diseases, the axis influences neuroinflammation, synaptic plasticity, and neuronal survival through various signaling cascades, including PI3K/AKT, MAPK, and JAK/STAT pathways. Emerging evidence suggests that modulating this axis could provide neuroprotective effects and potentially alleviate cognitive symptoms. This review highlights the potential of the CXCL12/CXCR4/CXCR7 axis as a therapeutic target for addressing CI in neurodegenerative diseases. It also underscores the need for further research to fully elucidate its role and develop effective interventions, potentially leading to improved clinical management strategies for these devastating disorders.

The influence of genotype on the natural history of types 1 - 3 spinal muscular atrophy.

The severity of spinal muscular atrophy (SMA) is inversely correlated with the number of survival of motor neuron 2 (SMN2) copies an individual has. This observational, retrospective analysis of natural history data included untreated individuals with a genetic diagnosis of types 1-3 SMA and stratified disease-related characteristics by SMN2 copy number. The outcomes investigated were time to: death, permanent ventilation, respiratory support, feeding support, scoliosis surgery, and achievement and loss of motor milestones. Of 134 individuals; 33 had two SMN2 copies and 101 had 3 or more copies. Survival was linked to increasing SMN2 copy number: mean age at death for individuals with two SMN2 copies was 8 months (standard deviation [SD]: 4 months) and 10 years (SD: 5 months) for individuals with three copies, and no deaths were reported in individuals with ≥4 SMN2 copies. Increasing SMN2 copy number was linked to a longer time to permanent ventilation, respiratory support, feeding support, and scoliosis, as well as loss of motor milestones. SMA disease-related endpoints showed distinct patterns between groups with differing SMN2 copy numbers. Prediction and assessment of disease progression may be stratified by SMN2 copy number, which will be important for evaluating the impact of treatment.

The role of mitochondrial remodeling in neurodegenerative diseases.

Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.

Abstract TP357: Mitochondrial intercellular transfer via platelets after physical training exerts neuro-glial protection against cerebral ischemia.

Background: Despite the effectiveness of immediate treatment, such as thrombolytic therapy, after a stroke, many patients are unable to benefit due to time restrictions. In an aging society, sarcopenia, a condition characterized by reduced muscle volume, is emerging as a significant issue, often contributing to poor recovery after stroke. Our study examined the role of mitochondria, which are abundant in muscle, and their migration during exercise in the context of stroke recovery. Methods: We used mice models to simulate chronic hypoperfusion and distal middle cerebral artery occlusion. We also conducted in vitro studies with rat primary cells, co-cultured with a nonlethal concentration of CoCl 2 and oxygen-glucose deprivation. Results: We found that 28 days post-hypoperfusion, there was a progression in white matter injury, including myelin loss, astroglial formation, and memory disorder. However, treadmill training protected against these damages. In cases of acute ischemia, training improved complications and reduced glial activation. We observed increased mitochondria in muscle and blood due to training, which migrated between tissues using platelets. In vitro analysis revealed that adding muscle mitochondria improved the survival of neurons, astrocytes, and oligodendrocytes. Most importantly, we found that mitochondrial transfusion from treadmill-trained mice platelet improved ischemic white matter injury and post-stroke complications. Conclusions: The study showed mitochondria as part of the secretome, essential for regulating cell interactions. It explored mitochondrial secretion, transfer between cells, and dynamics influencing ischemic tissue. The protective effects of remote ischemic preconditioning might be linked to muscle-derived mitochondria, a recent phenomenon. Unlike conventional platelet transfusion, mitochondria administration even from cryopreserved platelets shows brain protection effect. Therefore, this suggests that the advantage of this therapy is that mitochondria can be extracted from platelets that could not be used for transfusion and used for treatment. Our study suggests it could be a promising new treatment for reducing post-stroke complications and vascular dementia.

Sirtuin1 in Spinal Cord Injury: Regulatory Mechanisms, Microenvironment Remodeling and Therapeutic Potential.

Spinal cord injury (SCI) is a complex central nervous system disorder characterized by multifaceted pathological processes, including inflammation, oxidative stress, programmed cell death, autophagy, and mitochondrial dysfunction. Sirtuin 1 (Sirt1), a critical NAD+-dependent deacetylase, has emerged as a promising therapeutic target for SCI repair due to its potential to protect neurons, regulate glial and vascular cells, and optimize the injury microenvironment. However, the regulatory roles of Sirt1 in SCI are complex and challenging, as its effects vary depending on activation timing, expression levels, and cell types. A systematic literature review was conducted using PubMed, Scopus, and Web of Science to identify studies investigating Sirt1 in SCI. Relevant publications were analyzed to synthesize current evidence on Sirt1's mechanisms, therapeutic effects, and challenges in SCI repair. Sirt1 exerts broad regulatory effects across diverse pathological processes and cell types post-SCI. It promotes neuronal survival and axonal regeneration, modulates astrocytes and microglia to resolve inflammation, supports oligodendrocyte-mediated myelination, and enhances vascular endothelial function. Proper Sirt1 activation may mitigate secondary injury, whereas excessive or prolonged activation could impair inflammatory resolution or disrupt cellular homeostasis. This review highlights Sirt1 activation as potential therapies, but challenges include optimizing spatiotemporal activation and addressing dual roles in different cell types. Targeting Sirt1 represents a viable strategy for SCI repair, given its multifaceted regulation of neuroprotection, immunomodulation, and tissue remodeling. However, translating these findings into therapies requires resolving critical issues such as cell type-specific delivery, precise activation timing, and dosage control. This review provides a theoretical foundation and practical insights for advancing Sirt1-based treatments for SCI.

Microglia and Astrocytes in Postnatal Neural Circuit Formation.

Over the past two decades, microglia and astrocytes have emerged as critical mediators of neural circuit formation. Particularly during the postnatal period, both glial subtypes play essential roles in orchestrating nervous system development through communication with neurons. These functions include regulating synapse elimination, modulating neuronal density and activity, mediating synaptogenesis, facilitating axon guidance and organization, and actively promoting neuronal survival. Despite the vital roles of both microglia and astrocytes in ensuring homeostatic brain development, the extent to which the postnatal functions of these cells are regulated by sex and the manner in which these glial cells communicate with one another to coordinate nervous system development remain less well understood. Here, we review the critical functions of both microglia and astrocytes independently and synergistically in mediating neural circuit formation, focusing our exploration on the postnatal period from birth to early adulthood.

Electroacupuncture ameliorated locomotor symptoms in MPTP-induced mice model of Parkinson's disease by regulating autophagy via Nrf2 signaling.

Parkinson's disease (PD) is a prevalent and challenging neurodegenerative disorder, and may involve impaired autophagy. Nuclear factor erythroid-2-related factor 2 (Nrf2) is crucial for regulating autophagy-related genes and maintaining cellular homeostasis. Electroacupuncture (EA), a complementary and alternative therapy for PD, has gained widespread clinical application. In this study, we investigate whether EA at Baihui (GV20) and Taichong (LR3) acupoints modulates autophagy through the Nrf2 pathway, providing neuroprotection in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice. Using wild-type and Nrf2 knockout (KO) mice, we examined EA's effects on dopaminergic neuron survival, α-synuclein expression, motor function and the underlying mechanisms. Results showed that EA treatment significantly reduced dopaminergic neuron loss and α-synuclein expression, and improved motor deficits while restoring autophagy, as evidenced by increased autophagy markers (Atg7, LC3II) and decreased p62 levels. Transmission electron microscopy confirmed a rise in autophagosomes and lysosomes in the MPTP + EA group. EA also enhanced nuclear Nrf2 expression and activated Nrf2 signaling. Importantly, Nrf2 KO mice did not exhibit neuroprotection or increased autophagy-related proteins following EA treatment. In conclusion, our research demonstrated that EA ameliorated defective autophagy and activated the Nrf2 signaling pathway, which collectively contribute to its neuroprotective effects against MPTP-induced neurotoxicity.NEW & NOTEWORTHY In this study, we explored the potential mechanism of electroacupuncture (EA) therapy at the GV20 and LR3 acupoints of Parkinson's disease (PD). We demonstrated EA therapy's neuroprotective effect on PD, through ameliorating defective autophagy and activating the nuclear factor erythroid-2-related factor 2 (Nrf2) signaling pathway whereas the regulation of EA on autophagy was absent in Nrf2 knockout (KO) mice. Our study not only provides new insights into the therapeutic mechanisms of EA but also suggests a promising strategy for PD treatment.

Selective inhibitors of the TrkC.T1 receptor reduce retinal inflammation and delay neuronal death in a model of retinitis pigmentosa.

The heterogeneity of receptor isoforms can cause an apparent paradox where each isoform can promote different or even opposite biological pathways. One example is the neurotrophin receptor TrkC. The trkC mRNA translates a full-length receptor tyrosine kinase (TrkC-FL) whose activation by the growth factor NT3 promotes neuronal survival. In some diseases, the trkC mRNA is spliced to a kinase-truncated isoform (TrkC.T1) whose activation by NT3 up-regulates tumor necrosis factor alpha (TNF-α) causing neurotoxicity. Since TrkC.T1 expression is significantly increased at the onset of neurodegeneration, we hypothesized that in disease TrkC.T1-mediated toxicity prevails over TrkC-FL-mediated survival. To study this, we developed small molecules that selectively antagonize NT3-driven TrkC.T1 neurotoxicity without compromising TrkC-FL survival. In a genetic mouse model of retinitis pigmentosa, therapeutic administration of TrkC.T1 antagonists prevents elevation of TNF-α and reduces photoreceptor neuronal death. This work demonstrates the importance of accounting for functional and structural heterogeneity in receptor-ligand interactions, illustrates chemical biology strategies to develop isoform-selective agents, validates TrkC.T1 as a druggable target, and expands the therapeutic concept of reducing neurotoxicity as a strategy to achieve neuroprotection.

Determination of Total Flavonoid Content and Phenolic Content, Antioxidant Assay, and Antiepileptic Activity of Achillea millefolium Extract

Objectives This study aimed to evaluate the antioxidant and antiepileptic potential of the ethanolic extract of Achillea millefolium aerial parts. Antioxidant activity was measured using DPPH photometric assay, and flavonoid content was quantified via the aluminum chloride method. The extract's neuroprotective effect was assessed using the pentylenetetrazole (PTZ)-induced seizure model, along with immunohistochemical (IHC) analysis and hematoxylin & eosin (H&E) staining. Methods The antioxidant potential of the extract was determined through DPPH radical scavenging activity, while flavonoid content was assessed as quercetin equivalents (QE). The in vivo antiepileptic activity was evaluated in mice using the PTZ-induced seizure model. Key biomarkers of oxidative stress, including glutathione (GSH), glutathione-S-transferase (GST), catalase, and lipid peroxidation (LPO), were measured to evaluate the extract's ability to ameliorate PTZ-induced oxidative stress. Results The extract demonstrated notable antioxidant activity, with 72% scavenging activity observed at 900 µg/mL. Flavonoid content was determined to be 39.45 ± 1.84 µg QE/mg. In the PTZ-induced seizure model, Achillea millefolium extract at 400 mg/kg and 600 mg/kg significantly reduced neuroinflammatory markers and oxidative stress, as evidenced by decreased LPO and increased levels of GSH, GST, and catalase. IHC and H&E staining revealed neuroprotective effects, including reduced neuroinflammation and enhanced neuronal survival. Conclusion The ethanolic extract of Achillea millefolium exhibited strong antioxidant and neuroprotective properties, effectively mitigating PTZ-induced seizures, oxidative stress, and inflammatory responses. These findings suggest its potential as a natural alternative for epilepsy treatment.

Electroacupuncture improves cognitive impairment after subarachnoid hemorrhage in rats through the PI3K/AKT signaling pathway.

Cognitive impairment (CI) is highly prevalent in subarachnoid hemorrhage (SAH) patients. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway plays a critical role in neuronal survival in a variety of central nervous system injuries. This study aimed to determine whether electroacupuncture (EA) at Yintang and LI20 ameliorates SAH-CI in a rat model and to examine whether it modulates the PI3K/AKT pathway by administering a PI3K inhibitor (LY294002) versus dimethyl sulfoxide (DMSO) vehicle. Notably, 129 male Sprague-Dawley rats were divided into Blank, Sham, SAH and SAH + EA groups (Experiment 1, n = 54) and SAH, SAH + EA, SAH + LY294002, SAH + EA + LY294002 and SAH + EA + DMSO groups (Experiment 2, n = 75). Garcia scoring was used to evaluate neurological function. The moisture content of the rat brain was determined by dry‒wet method. The Morris water maze was used to assess learning and memory function. Pathological changes in neurons in the hippocampus were observed via hematoxylin-eosin (H&E) staining. The number of surviving neurons and the percentage of apoptotic cells in the hippocampus were detected via Nissl and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The expression of PI3K/AKT pathway-related proteins was detected via Western blotting. The results indicated that EA intervention after SAH reduced brain water content, enhanced Garcia scores, improved neurological function and behavioral markers of CI, and increased the number of surviving neurons in the hippocampus. Moreover, EA significantly increased the expression of AKT, phosphorylated (p)-AKT, PI3K, p-PI3K, glycogen synthase kinase (GSK)-3β, p-GSK-3β and B cell lymphoma (Bcl)-2 proteins, and decreased the expression of Bcl-2-associated X (Bax) and caspase-3. In addition, the effects of EA were abolished by LY294002. EA appeared to improve CI in a rat model of SAH through the activation of the PI3K/AKT pathway.

NGF in Neuropathic Pain: Understanding Its Role and Therapeutic Opportunities

Nerve growth factor (NGF) is one of the essential components that have been implicated in the pathophysiology of neuropathic pain, a condition that develops following nerve injury or dysfunction. This neurotrophin is critical for the survival and maintenance of sensory neurons, and its dysregulation has been implicated in the sensitization of pain pathways. NGF interacts with its receptor TrkA and p75NTR to activate intracellular signaling pathways associated with nociception and the emergence of allodynia and hyperalgesia. Therapeutic approaches employing neutralizing antibodies and molecule inhibitors have been highly effective at both preclinical and clinical levels, hence giving hope again for the use of NGF as an important biomarker and therapeutic target in the management of neuropathic pain. By exploiting the unique properties of NGF and its interactions within the nervous system, new therapeutic modalities could be designed to enhance efficacy while minimizing side effects. In conclusion, taking advantage of the multifaceted dynamics of NGF could provide effective pain management therapies to finally respond to the unmet needs of patients experiencing neuropathic pain.

The Effect of Repetitive Transcranial Magnetic Stimulation Treatment on Plasma BDNF Concentration and Executive Functions in Parkinson’s Disease: A Theoretical Translational Medicine Approach

Parkinson’s disease (PD) neuropathology is marked by the selective loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by the widespread involvement of central and peripheral structures. Brain-derived neurotrophic factor (BDNF), a neurotrophin crucial for the survival of dopaminergic neurons, plays a pivotal role in neuronal and glial development, neuroprotection, and the modulation of synaptic plasticity. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive technique, enhances neurotransmitter release, trans-synaptic efficacy, signaling pathways, gene transcription, neuroplasticity, and neurotrophism. Evidence supports that high-frequency rTMS increases BDNF expression and improves task-specific cognitive deficits in PD patients. This article outlines a detailed protocol to investigate whether rTMS targeting the dorsolateral prefrontal cortex bilaterally induces changes in plasma BDNF levels, the plasma-derived exosomal BDNF concentration, and executive functions in individuals with PD. Identifying non-invasive interventions that effectively modulate the neurobiological mechanisms underlying cognitive and behavioral functions is critical for addressing cognitive impairments and mitigating disease progression in the PD population. This study aims to advance translational research by identifying biomarkers and developing therapeutic strategies for future applications in neurodegenerative diseases.

Recent advancements in the understanding of the alterations in mitochondrial biogenesis in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurodegenerative disease characterized by progressive memory loss and cognitive decline. The processes underlying the pathophysiology of AD are still not fully understood despite a great deal of research. Since mitochondrial dysfunction affects cellular energy metabolism, oxidative stress, and neuronal survival, it is becoming increasingly clear that it plays a major role in the development of AD. This review summarizes the recent developments of mitochondrial dysfunction in AD, emphasizing mitochondrial biogenesis, dynamics, axonal transport, interactions between endoplasmic reticulum and mitochondria, mitophagy, and mitochondrial proteostasis. It emphasizes how tau and amyloid-beta (Aβ) proteins worsen mitochondrial and synaptic dysfunction by impairing adenosine triphosphate (ATP) synthesis, causing oxidative stress, and upsetting equilibrium. Additionally, important processes controlling mitochondrial activity and their correlation to the brain health are also discussed. One of the promising therapeutic approaches to lessen neurodegeneration and cognitive decline in AD is to improve mitochondrial activity. This study highlights possible directions for creating focused therapies to impede the advancement of AD through incorporating knowledge of mitochondrial biogenesis and its related mechanisms.

The role of neurotrophic factors in retinal ganglion cell resiliency

Many retinal diseases are characterized by direct or indirect retinal ganglion cell (RGC) neurodegeneration. In glaucoma and optic nerve neuropathies, RGCs are the primary affected cells, whereas in photoreceptor dystrophies, RGC loss is secondary to the death of rods and cones. The death of RGCs in either case will irreversibly cause loss of vision, as RGCs are the sole output neurons of the retina. RGC neurodegeneration affects certain neurons preferentially, resulting in subpopulations of resilient and susceptible cells. Neurotrophins (NTs) are known to mediate neuronal survival through the downstream activation of various anti-apoptotic pathways. In this review, we summarize the current methods of RGC identification and quantification in animal models of direct or indirect neurodegeneration, and describe the advantages and disadvantages associated with these techniques. Using these techniques, multiple studies have uncovered the potential role of NTs in protecting RGCs during direct neurodegeneration, with BDNF and NGF delivery promoting RGC survival in models of experimental glaucoma. Many fewer studies have addressed similar questions in retinal diseases where RGC loss is secondary to photoreceptor degeneration, yielding conflicting results. Our analysis suggests that these seemingly contradictory results can be explained by the varying onset and geographic distribution of photoreceptor death.