Effects In Neurological Disorders Research Articles

Potential Therapeutic Approach using Aromatic l-amino Acid Decarboxylase and Glial-derived Neurotrophic Factor Therapy Targeting Putamen in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative illness characterized by specific loss of dopaminergic neurons, resulting in impaired motor movement. Its prevalence is twice as compared to the previous 25 years and affects more than 10 million individuals. Lack of treatment still uses levodopa and other options as disease management measures. Treatment shifts to gene therapy (GT), which utilizes direct delivery of specific genes at the targeted area. Therefore, the use of aromatic L-amino acid decarboxylase (AADC) and glial-derived neurotrophic factor (GDNF) therapy achieves an effective control to treat PD. Patients diagnosed with PD may experience improved therapeutic outcomes by reducing the frequency of drug administration while utilizing provasin and AADC as dopaminergic protective therapy. Enhancing the enzymatic activity of tyrosine hydroxylase (TH), glucocorticoid hormone (GCH), and AADC in the striatum would be useful for external L-DOPA to restore the dopamine (DA) level. Increased expression of glutamic acid decarboxylase (GAD) in the subthalamic nucleus (STN) may also be beneficial in PD. Targeting GDNF therapy specifically to the putaminal region is clinically sound and beneficial in protecting the dopaminergic neurons. Furthermore, preclinical and clinical studies supported the role of GDNF in exhibiting its neuroprotective effect in neurological disorders. Another Ret receptor, which belongs to the tyrosine kinase family, is expressed in dopaminergic neurons and sounds to play a vital role in inhibiting the advancement of PD. GDNF binding on those receptors results in the formation of a receptor-ligand complex. On the other hand, venous delivery of recombinant GDNF by liposome-based and encapsulated cellular approaches enables the secure and effective distribution of neurotrophic factors into the putamen and parenchyma. The current review emphasized the rate of GT target GDNF and AADC therapy, along with the corresponding empirical evidence.

Exploring the mechanisms of kaempferol in neuroprotection: Implications for neurological disorders.

Kaempferol, a flavonoid compound found in various fruits, vegetables, and medicinal plants, has garnered increasing attention due to its potential neuroprotective effects in neurological diseases. This research examines the existing literature concerning the involvement of kaempferol in neurological diseases, including stroke, Parkinson's disease, Alzheimer's disease, neuroblastoma/glioblastoma, spinal cord injury, neuropathic pain, and epilepsy. Numerous in vitro and in vivo investigations have illustrated that kaempferol possesses antioxidant, anti-inflammatory, and antiapoptotic properties, contributing to its neuroprotective effects. Kaempferol has been shown to modulate key signaling pathways involved in neurodegeneration and neuroinflammation, such as the PI3K/Akt, MAPK/ERK, and NF-κB pathways. Moreover, kaempferol exhibits potential therapeutic benefits by enhancing neuronal survival, attenuating oxidative stress, enhancing mitochondrial calcium channel activity, reducing neuroinflammation, promoting neurogenesis, and improving cognitive function. The evidence suggests that kaempferol holds promise as a natural compound for the prevention and treatment of neurological diseases. Further research is warranted to elucidate the underlying mechanisms of action, optimize dosage regimens, and evaluate the safety and efficacy of this intervention in human clinical trials, thereby contributing to the advancement of scientific knowledge in this field.

Sphingosine-1-Phosphate Receptor Modulator – Siponimod: An Evaluation to Ameliorate Aluminium Chloride Induced Behavioural Change and Biochemical effects

Introduction: Alzheimer's disease (AD) is a neurodegenerative condition characterised by the gradual loss of hippocampal and cortical neurons, resulting in diminished memory and cognitive function. Siponimod (SPM) a selective modulator of sphingosine 1-phosphate receptor subtype 1 and 5(S1P1,S1P5 receptors), was found to have neuroprotective effect in neurological disorders. The present study was conducted to evaluate its beneficial effects in AD. Materials and Methods: In-silico molecular docking and molecular dynamic simulation studies were carried to know its potential interactions with selected target proteins. In-vivo study was conducted inthirty rats divided randomly into five groups with six rats per group: Control group received Carboxy methyl cellulose; disease group were administered aluminium chloride (AlCl3);standard group received rivastigmine (RVST) with AlCl3; and the test groups received SPM (0.05mg/kg and 0.2mg/kg) with AlCl3. Morris water maze test and elevated plus maze was used to evaluate learning and memory. Behavioural changes and biochemical parameters estimation were performed at the end of experiment. Results: The molecular docking study using selected protein and ligands showed higher docking score and stable interactions at acetylcholinesterase (AChE) protein with SPM.Behavioural studies showed: decrease in transfer latency time in elevated plus maze; decrease in time to reach target platform and increase in time spent in target quadrant in Morris water maze test in SPM treated rats. Biochemical evaluation showed marked decrease in malondialdehyde (MDA), nitrite, myeloperoxidase (MPO)levels and increased antioxidant levels in SPM treated groups. SPM exhibited significant inhibitory activity onAChE. Conclusion: SPM was found to be effective in ameliorating AlCl3 induced AD. The observed benefits in restoring learning and memory were attributed to its inhibitory activity on AChE and its ability to suppress free radical mediated oxidative damage.

Effect of neonatal melatonin administration on behavioral and brain electrophysiological and redox imbalance in rats.

Melatonin (MLT) reportedly has beneficial effects in neurological disorders involving brain excitability (e.g., Epilepsy and Migraine) and behavioral patterns (e.g., Anxiety and Depression). This study was performed to investigate, in the developing rat brain, the effect of early-in-life administration of two different doses of exogenous MLT on behavioral (anxiety and memory) and electrophysiological (CSD analysis) aspects of brain function. Additionally, brain levels of malondialdehyde (MDA) and superoxide dismutase (SOD), both cellular indicators of redox balance status, were evaluated. We hypothesize that MLT differentially affects the behavioral and CSD parameters as a function of the MLT dose. Male Wistar rats received, from the 7th to the 27th postnatal day (PND), on alternate days, vehicle solution, or 10 mg/kg/or 40 mg/kg MLT (MLT-10 and MLT-40 groups), or no treatment (intact group). To perform behavioral and cognition analysis, from PND30 to PND32, they were tested in the open field apparatus, first for anxiety (PND30) and then for object recognition memory tasks: spatial position recognition (PND31) and shape recognition (PND32). On PND34, they were tested in the elevated plus maze. From PND36 to 42, the excitability-related phenomenon known as cortical spreading depression (CSD) was recorded, and its features were analyzed. Treatment with MLT did not change the animals' body weight or blood glucose levels. The MLT-10 treatment, but not the MLT-40 treatment, was associated with behaviors that suggest less anxiety and improved memory. MLT-10 and MLT-40 treatments, respectively, decelerated and accelerated CSD propagation (speed of 2.86 ± 0.14 mm/min and 3.96 ± 0.16 mm/min), compared with the control groups (3.3 ± 0.10 mm/min and 3.25 ± 0.11 mm/min, for the intact and vehicle groups, respectively; p < 0.01). Cerebral cortex levels of malondialdehyde and superoxide dismutase were, respectively, lower and higher in the MLT-10 group but not in the MLT40 group. Our findings suggest that MLT intraperitoneal administration during brain development may differentially act as an antioxidant agent when administered at a low dose but not at a high dose, according to behavioral, electrophysiological, and biochemical parameters.

Association of intestinal dysbiosis with susceptibility to multiple sclerosis: Evidence from different population studies (Review).

Understanding the relationship between microorganisms that live in our intestines and neuroinflammatory and neurodegenerative pathologies of the central nervous system (CNS) is essential, since they have been shown to have an immunomodulatory effect in neurological disorders, such as multiple sclerosis (MS). The gut microbiota can be affected by several environmental factors, including infections, physical and emotional stress and diet, the latter known as the main modulator of intestinal bacteria. An abrupt shift in the gut microbiota composition and function is known as dysbiosis, a state of local and systemic inflammation produced by pathogenic bacteria and its metabolites responsible for numerous neurological symptoms. It may also trigger neuronal damage in patients diagnosed with MS. Intestinal dysbiosis affects the permeability of the intestine, allowing chronic low-grade bacterial translocation from the intestine to the circulation, which may overstimulate immune cells and cells resident in the CNS, break immune tolerance and, in addition, alter the permeability of the blood-brain barrier (BBB). This way, toxins, inflammatory molecules and oxidative stress molecules can pass freely into the CNS and cause extensive damage to the brain. However, commensal bacteria, such as the Lactobacillus genus and Bacteroides fragilis, and their metabolites (with anti-inflammatory potential), produce neurotransmitters such as γ-aminobutyric acid, histamine, dopamine, norepinephrine, acetylcholine and serotonin, which are important for neurological regulation. In addition, reprogramming the gut microbiota of patients with MS with a healthy gut microbiota may help improve the integrity of the gut and BBB, by providing clinically protective anti-inflammatory effects and reducing the disease's degenerative progression. The present review provides valuable information about the relationship between gut microbiota and neuroinflammatory processes of the CNS. Most importantly, it highlights the importance of intestinal bacteria as an environmental factor that may mediate the clinical course of MS, or even predispose to the outbreak of this disease.

Hesperetin ameliorates spinal cord injury by inhibiting NLRP3 inflammasome activation and pyroptosis through enhancing Nrf2 signaling.

Neuroinflammation is a prominent feature of traumatic spinal cord injuries (SCIs). Hesperetin exhibits anti-inflammatory effects in neurological disorders; however, the potential neuroprotective effects of hesperetin in cases of SCI remain unclear. Sprague-Dawley rats with C5 hemi-contusion injuries were used as an SCI model. Hesperetin was administered to the experimental rats in order to investigate its neuroprotective effects after SCI, and BV2 cells were pretreated with hesperetin or silencing of nuclear factor erythroid 2-related factor 2 (siNrf2), and then stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). The therapeutic impact and molecular mechanism of hesperetin were elucidated in a series of in vivo and in vitro investigations conducted using a combination of experiments. The results of the present in vivo experiment indicated that hesperetin improved functional recovery and protected spinal cord tissue after SCI. Hesperetin attenuated oxidative stress and microglial activation, lowered malondialdehyde (MDA) levels, and elevated catalase (CAT), glutathione (GSH)-Px, and superoxide dismutase (SOD) levels. Moreover, hesperetin downregulated the expression of advanced oxygenation protein products (AOPPs), ionized calcium-binding adapter molecule 1 (Iba-1), NOD-like receptor protein 3 (NLRP3), and interleukin-1 beta (IL-1β), but increased the expression of Nrf2. In vitro studies have shown that hesperetin inhibits the generation of reactive oxygen species (ROS), as well as the neuroinflammation associated with the upregulation of Nrf2 and heme oxygenase-1 (HO-1) in BV2 cells. The results of the present study indicated that hesperetin inhibited BV2 cell pyroptosis and significantly blocked the expression of NLRP3 inflammasome proteins (NLRP3 Caspase-1 p10 apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain [ASC]) and pro-inflammatory mediators (IL-18, IL-1β). Furthermore, the silencing of Nrf2 by small interfering ribonucleic acid (siRNA) partially abolished its antioxidant effect in the aforementioned cell experiments. Collectively, these findings illustrate that through an increase in Nrf2 signaling hesperetin reduces oxidative stress and neuroinflammation by suppressing NLRP3 inflammasome activation and pyroptosis.

Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model.

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1β concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1β concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation.

Challenges and Discoveries in Polypharmacology of Neurodegenerative Diseases.

Neurological disorders are composed of several diseases that affect the central and peripheral nervous system; among these are neurodegenerative diseases, which lead to neuronal death. Many of these diseases have treatment for the disease and symptoms, leading patients to use several drugs that cause side effects. The search for new treatments has led to the investigation of multi-target drugs. This review aimed to investigate in the literature the multi-target effect in neurological disorders through an in silico approach. Studies were reviewed on the diseases such as epilepsy, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, cerebral ischemia, and Parkinson's disease. As a result, the study emphasize the relevance of research by computational techniques such as quantitative structure-activity relationship (QSAR) prediction models, pharmacokinetic prediction models, molecular docking, and molecular dynamics, besides presenting possible drug candidates with multi-target activity. It was possible to identify several targets with pharmacological activities. Some of these targets had diseases in common such as carbonic anhydrase, acetylcholinesterase, NMDA, and MAO being relevant for possible multi-target approaches.

Necrosulfonamide Alleviates Acute Brain Injury of Intracerebral Hemorrhage via Inhibiting Inflammation and Necroptosis.

ObjectiveIntracerebral hemorrhage (ICH) is the most lethal subtype of stroke, without effective treatment. Necrosulfonamide (NSA), a specific inhibitor for mixed lineage kinase domain-like protein, has been reported to exert neuroprotective effects in neurological diseases by ameliorating neuroinflammation and necroptosis. We hypothesized that NSA would alleviate acute brain injury and improve behavioral outcomes after ICH.Materials and MethodsMale adult C57BL/6 mice were assigned randomly into three groups. In vehicle and treatment groups, animals were injected with collagenase VII to induce ICH. The solvent (0.25% DMSO) and NSA (5 mg/kg) were administrated intraperitoneally twice a day, respectively. The sham group was injected with saline and administrated with DMSO. The brain hematoma volume, inflammatory factors, and blood-brain barrier permeability were measured on day 3 after the operation. Fluorescent double immunostaining was performed to evaluate the neuronal death. Neurological functions were assessed.ResultsIn the NSA group, the hematoma size was significantly reduced, inflammatory cells and cytokines were suppressed, and the blood-brain barrier was protected compared to vehicle controls. NSA dramatically reduced the death of neurons and improved the performance of neurological functions after ICH.ConclusionNecrosulfonamide has a neuroprotective role in alleviating acute brain injury in a mouse ICH model, and this is associated with reduced neuroinflammation and necroptosis.

Dietary supplements in neurological diseases and brain aging.

A healthy diet shapes a healthy mind. Diet quality has a strong association with brain health. Diet influences the onset and consequences of neurological diseases, and dietary factors may influence mental health at individual and population level. The link between unhealthy diet, impaired cognitive function and neurodegenerative diseases indicates that adopting a healthy diet would ultimately afford prevention and management of neurological diseases and brain aging. Neurodegenerative diseases are of multifactorial origin and result in progressive loss of neuronal function in the brain, leading to cognitive impairment and motoneuron disorders. The so-called Mediterranean diet (MedDiet) with its healthy ingredients rich in antioxidant, anti-inflammatory, immune, neuroprotective, antidepressant, antistress and senolytic activity plays an essential role in the prevention and management of neurological diseases and inhibits cognitive decline in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. The MedDiet also modulates the gut-brain axis by promoting a diversity of gut microbiota. In view of the importance of diet in neurological diseases management, this review focuses on the dietary components, natural compounds and medicinal plants that have proven beneficial in neurological diseases and for brain health. Among them, polyphenols, omega-3 fatty acids, B vitamins and several ayurvedic herbs have promising beneficial effects.

Altered diffusivity of the subarachnoid cisterns in the rat brain following neurological disorders

BackgroundAlthough changes in diffusion characteristics of the brain parenchyma in neurological disorders are widely studied and used in clinical practice, the change in diffusivity in the cerebrospinal fluid (CSF) system is rarely reported. In this study, free water diffusion in the subarachnoid cisterns and ventricles of the rat brain was examined using diffusion magnetic resonance imaging (MRI), and the effects of neurological disorders on diffusivity in CSF system were investigated. MethodsDiffusion MRI and T2-weighted images were obtained in the intact rats, 24 h after ischemic stroke, and 50 days after mild traumatic brain injury (mTBI). We conducted the assessment of diffusivity in the rat brain in the subarachnoid cisterns around the midbrain, as well as the lateral ventricles. One-way ANOVA and Kruskal–Wallis test were used to evaluate the change in mean diffusivity (MD) and MD histogram, respectively, in CSF system following different neurological disease. ResultsA significant decrease in the mean MD value of the subarachnoid cisterns was observed in the stroke rats compared with the intact and mTBI rats (p < 0.005). In addition, the skewness (p < 0.002), maximum MD (p < 0.002), and MD percentiles (p < 0.002) in the stroke rats differed significantly from those in the intact and mTBI rats. By contrast, no difference was observed in the mean MD value of the lateral ventricles among three groups of rats. We proposed that the assessment of the subarachnoid cisterns, rather than the lateral ventricles, in the rat brain would be useful in providing diffusion information in the CSF system. ConclusionsAlterations in MD parameters of the subarachnoid cisterns after stroke provide evidence that brain injury may alter the characteristics of free water diffusion not only in the brain parenchyma but also in the CSF system.

Coenzyme Q10 effects in neurological diseases.

Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).

Coenzyme Q10 effects in neurological diseases

Coenzyme Q10 (CoQ10), a lipophilic substituted benzoquinone, is present in animal and plant cells. It is endogenously synthetized in every cell and involved in a variety of cellular processes. CoQ10 is an obligatory component of the respiratory chain in inner mitochondrial membrane. In addition, the presence of CoQ10 in all cellular membranes and in blood. It is the only endogenous lipid antioxidant. Moreover, it is an essential factor for uncoupling protein and controls the permeability transition pore in mitochondria. It also participates in extramitochondrial electron transport and controls membrane physicochemical properties. CoQ10 effects on gene expression might affect the overall metabolism. Primary changes in the energetic and antioxidant functions can explain its remedial effects. CoQ10 supplementation is safe and well-tolerated, even at high doses. CoQ10 does not cause any serious adverse effects in humans or experimental animals. New preparations of CoQ10 that are less hydrophobic and structural derivatives, like idebenone and MitoQ, are being developed to increase absorption and tissue distribution. The review aims to summarize clinical and experimental effects of CoQ10 supplementations in some neurological diseases such as migraine, Parkinson´s disease, Huntington´s disease, Alzheimer´s disease, amyotrophic lateral sclerosis, Friedreich´s ataxia or multiple sclerosis. Cardiovascular hypertension was included because of its central mechanisms controlling blood pressure in the brainstem rostral ventrolateral medulla and hypothalamic paraventricular nucleus. In conclusion, it seems reasonable to recommend CoQ10 as adjunct to conventional therapy in some cases. However, sometimes CoQ10 supplementations are more efficient in animal models of diseases than in human patients (e.g. Parkinson´s disease) or rather vague (e.g. Friedreich´s ataxia or amyotrophic lateral sclerosis).

Insights Into the Role of CSF1R in the Central Nervous System and Neurological Disorders.

The colony-stimulating factor 1 receptor (CSF1R) is a key tyrosine kinase transmembrane receptor modulating microglial homeostasis, neurogenesis, and neuronal survival in the central nervous system (CNS). CSF1R, which can be proteolytically cleaved into a soluble ectodomain and an intracellular protein fragment, supports the survival of myeloid cells upon activation by two ligands, colony stimulating factor 1 and interleukin 34. CSF1R loss-of-function mutations are the major cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) and its dysfunction has also been implicated in other neurodegenerative disorders including Alzheimer’s disease (AD). Here, we review the physiological functions of CSF1R in the CNS and its pathological effects in neurological disorders including ALSP, AD, frontotemporal dementia and multiple sclerosis. Understanding the pathophysiology of CSF1R is critical for developing targeted therapies for related neurological diseases.

Resveratrol loaded nanoparticles attenuate cognitive impairment and inflammatory markers in PTZ-induced kindled mice

Resveratrol has been found to exert protective effects in neurological disorders, including epilepsy. However, its poor bioavailability and difficulty in reaching the brain’s targeted location reduce resveratrol’s efficacy substantially. The side effects due to the higher concentration of drugs are another matter of concern. The objective of the present study is to propose solutions to these issues by encapsulating resveratrol in glutathione-coated collagen nanoparticles’ core. The collagen nanoparticles increase the resveratrol’s bioavailability, and glutathione helps in the passage of the encapsulated resveratrol to the target location in the brain. The concentration also substantially reduces due to resveratrol’s encapsulation in glutathione-coated collagen nanoparticles. The encapsulated resveratrol is termed nanoresveratrol. The effectiveness of nanoresveratrol on epilepsy seizures was evaluated through histopathological examinations, ELISA tests, and qRT-PCR tests on the hippocampus of the kindled mice. The novelty of the present study thus lies in (i) the synthesis of nanoresveratrol using glutathione-coated collagen nanoparticles and (ii) the application of synthesized nanoresveratrol in the treatment of epilepsy. The study’s outcome shows that nanoresveratrol has a favorable impact in reducing cognitive impairment in kindled mice, and it is more effective in controlling epilepsy seizures than resveratrol. The p-values of all the nanoresveratrol-given groups of mice (compared with the diseased group) were substantially smaller (∼10-4 to 10-2) than the significance level (0.05), indicating that the nanoresveratrol-given groups are significantly different from the diseased group, i.e., the nanoresveratrol has a significant effect on the mice. The concentration of resveratrol also decreases substantially in the proposed nanoformulation. It was observed that even 0.4 mg/kg of nanoformulation of resveratrol is performing better than 40 mg/kg of resveratrol.

Microglial Exosomes in Neurodegenerative Disease.

Microglia play an important role in neurodegenerative disease [i.e., Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS)]. These diseases share some similar pathological changes and several microglia-associated processes, including immune response, neuroinflammation, phagocytosis, elimination of synapses et al. Microglia in the central nervous system (CNS) has been described as having both destructive and protective effects in neurological disorders. Besides, considerable evidence also indicates that microglia play a significant role in neurogenesis, neuronal cell death, and synaptic interactions. The communication between microglia and neurons is of vital role in regulating complex functions which are key to appropriate the activity of the brain. Accumulating studies have also demonstrated that exosomes with sizes ranging from 40–100 nm, released by microglia, could serve as key mediators in intercellular signaling. These exosomes, identified in terms of cellular origin in many kinds of biological fluids, exert their effects by delivering specific cargos such as proteins, microRNAs (miRNAs), and mRNAs. It was shown that microglial exosomes could transport to and be uptake by neurons, which may either be beneficial or instead, detrimental to CNS diseases. The focus of this review is to summarize the involvement of microglial exosomes in critical pathologies associated with neurodegenerative disease and how they contribute to these disorders, including PD, AD, and ALS. We also review the application of microglia exosomes as potential biomarkers in monitoring disease progression, as well as focusing on their roles as drug delivery vehicles in treating neurodegenerative disorders.

Hypothermia promotes synaptic plasticity and protective effects in neurological diseases.

Hypothermia promotes synaptic plasticity and protective effects in neurological diseases.

Evaluation of Efferent Auditory System and Hearing Quality in Parkinson's Disease: Is the Difficulty in Speech Understanding in Complex Listening Conditions Related to Neural Degeneration or Aging?

Purpose The effects of neurological diseases on the auditory system have been a notable issue for investigators because the auditory pathway is closely associated with neural systems. The purposes of this study are to evaluate the efferent auditory system function and hearing quality in Parkinson's disease (PD) and to compare the findings with age-matched individuals without PD to present a perspective on aging. Method The study included 35 individuals with PD (mean age of 48.50 ± 8.00 years) and 35 normal-hearing peers (mean age of 49 ± 10 years). The following tests were administered for all participants: the first section of the Speech, Spatial and Qualities of Hearing Scale; pure-tone audiometry, speech audiometry, tympanometry, and acoustic reflexes; and distortion product otoacoustic emissions (DPOAEs) and contralateral suppression of DPOAEs. SPSS Version 25 was used for statistical analyses, and values of p < .05 were considered statistically significant. Results There were no statistically significant differences in the pure-tone audiometry thresholds and DPOAE responses between the individuals with PD and their normal-hearing peers (p = .732). However, statistically significant differences were found between the groups in suppression levels of DPOAEs and hearing quality (p < .05). In addition, a statistically significant and positive correlation was found between the amount of suppression at some frequencies and the Speech, Spatial and Qualities of Hearing Scale scores. Conclusions This study indicates that medial olivocochlear efferent system function and the hearing quality of individuals with PD were affected adversely due to the results of PD pathophysiology on the hearing system. For optimal intervention and follow-up, tasks related to hearing quality in daily life can also be added to therapies for PD.

Effects of Neurological Disorders on Bone Health.

Neurological diseases, particularly in the context of aging, have serious impacts on quality of life and can negatively affect bone health. The brain-bone axis is critically important for skeletal metabolism, sensory innervation, and endocrine cross-talk between these organs. This review discusses current evidence for the cellular and molecular mechanisms by which various neurological disease categories, including autoimmune, developmental, dementia-related, movement, neuromuscular, stroke, trauma, and psychological, impart changes in bone homeostasis and mass, as well as fracture risk. Likewise, how bone may affect neurological function is discussed. Gaining a better understanding of brain-bone interactions, particularly in patients with underlying neurological disorders, may lead to development of novel therapies and discovery of shared risk factors, as well as highlight the need for broad, whole-health clinical approaches toward treatment.

Bone marrow mesenchymal stem cells upregulate PI3K/AKT pathway and down-regulate NF-κB pathway by secreting glial cell-derived neurotrophic factors to regulate microglial polarization and alleviate deafferentation pain in rats

Deafferentation pain (DP), a typical neuropathic pain, occurs due to peripheral or central sensory nerve injury, which causes abnormal discharge of the upstream neurons or C fibers. Current treatment methods for DP have multiple side effects. Bone marrow mesenchymal stem cells (BMSC) have been used to treat neuropathic pain because of their ability to regulate neuroinflammation. Glial cell-derived neurotrophic factor (GDNF) is a neurotrophic mediator that exerts neuroprotective effects in neurological diseases. In this study, we investigated whether DP could be alleviated by BMSCs and the underlying mechanism. In vitro study, microglia was stimulated by lipopolysaccharide and then co-cultured with BMSC, GDNF or siRNA GDNF-BMSC. In vivo study, BMSC or siRNA GDNF-BMSC was transplanted intramedullarily on the 21st day after DP surgery. The expression of inflammatory-related factors were detected by RT-PCR and ELISA, RT-PCR,flow cytometry and immunofluorescence staining were performed to detect the expression of microglial surface markers, and Western blot was used to detect the expression levels of p-NF-kb, pPI3K, and pAKT. The pain-related behavioral changes were detected 7 days after transplantation. ELISA and RT-PCR results showed that the production of inflammatory cytokines in lipopolysaccharide-stimulated microglia and DP model plasma was downregulated, while anti-inflammatory mediators were upregulated significantly following pretreatment with BMSCs or GDNF. Flow cytometry, immunofluorescence staining, and RT-PCR results showed that BMSCs inhibited the microglial M1 phenotype and promoted the M2 phenotype by secreting GDNF. Furthermore, modulation functions of BMSCs involve inhibiting NF-κB while promoting PI3K /AKT signaling pathway activation. We found that our in vivo DP model was completely deafferent and BMSC administration clearly alleviated symptoms of DP. This function was also, at least partly, achieved by GDNF. The present studies demonstrate that BMSC can inhibit neuroinflammation by transforming microglial destructive M1 phenotype into regenerative M2 phenotype, and thus alleviate DP,likely by suppressing the NF-κB signaling pathway while promoting the PI3K/AKT signaling pathway activation through producing GDNF. The present findings are in support of the potential therapeutic application of BMSCs and the pharmaceutical application of GDNF for DP.