Unraveling the impact of Omega-3 polyunsaturated fatty acids on blood-brain barrier (BBB) integrity and glymphatic function.

Alzheimer's disease (AD) and other forms of dementia represent major public health challenges but effective therapeutic options are limited. Pathological brain aging is associated with microvascular changes and impaired clearance systems. The application of omega-3 polyunsaturated fatty acids (n-3 or omega-3 PUFAs) is one of the most promising nutritional interventions in neurodegenerative disorders from epidemiological data, clinical and pre-clinical studies. As essential components of neuronal membranes, n-3 PUFAs have shown neuroprotection and anti-inflammatory effects, as well as modulatory effects through microvascular pathophysiology, amyloid-beta (Aß) clearance and glymphatic pathways. This review meticulously explores these underlying mechanisms that contribute to the beneficial effects of n-3 PUFAs against AD and dementia, synthesizing evidence from both animal and interventional studies.

Macrofungal Mediated Biosynthesis of Silver Nanoparticles and Evaluation of Its Antibacterial and Wound-Healing Efficacy.

Recently, the utilization of biological agents in the green synthesis of nanoparticles has been given interest. In this study, silver nanoparticles were synthesized from an aqueous extract of macrofungus (mushroom), namely Phellinus adamantinus, in a dark room using 20 µL of silver nitrate. Biosynthesized silver nanoparticles were confirmed by analyzing them using a UV-Vis (ultraviolet-visible) spectrophotometer. The synthesized silver nanoparticles were optimized at different pH and temperatures with various dosages of AgNO3 (silver nitrate) and fungal extracts. The synthesized AgNPs (silver nanoparticles) were characterized using TEM (transmission electron microscopy) and EDX (energy-dispersive X-ray) analyses, which confirmed the presence of silver nanoparticles. The size of the nanosilver particles was found to be 50 nm with higher stability. The mycosynthesized AgNPs showed effective antibacterial activity against strains of Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (E. coli and Pseudomonas aeruginosa) bacteria. The minimum inhibitory concentration (MIC) was found to be 3.125 µg/mL by MIC assay. The MTT assay (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl-2H-tetrazolium bromide) was performed to study cytotoxicity, and reduced cell viability was recorded at 100 µg/mL. Silver-Polygalacturonic acid-Polyvinyl alcohol ((Ag-PGA)-PVA) nanofiber was prepared using the electrospinning method. The in vitro wound scratch assay was demonstrated to study the wound-healing efficacy of the prepared nanofiber. The wound-healing efficacy of the AgNP-incorporated nanofiber was found to be 20% after 24 h. This study will lay a platform to establish a unique route to the development of a novel nanobiomaterial and its application in antibacterial and wound-healing therapy.

The west meets the east - A need for a renaissance in brain, behavior, and immunity research.

Psychoneuroimmunology (PNI)-the burgeoning concept in recent years, can potentially contribute to developing effective treatments for mental health disorders. Despite the advancement in the modern pharmacological approach for mental disorders, especially Western medicine attributed explicitly to interacting with a specific target has given rise to unmet needs, and treatment failure has led to the proliferation and exploration of traditional and alternative therapies. As research into these exciting under-explored traditional treatment approaches continues to evolve at an unprecedented pace, the need to gain vital insights into the potentiality and mechanism of action in neuropsychiatric disorders has resulted in the current Special Issue. This Special Issue is devoted to psychoneuroimmunology, focusing on introducing the recent advances with traditional and alternative medications in East Asia at the interface of immunology, neurosciences, molecular psychiatry and behavioural medicine neurosciences.

Clinical efficacy and immune effects of acupuncture in patients with comorbid chronic pain and major depression disorder: A double-blinded, randomized controlled crossover study.

BACKGROUND: Depression and pain are highly comorbid and share biological mechanisms. Acupuncture is commonly used to manage both pain and depression, but the choice of acupoints for specific disorders differs. This study aimed to investigate whether specific acupuncture intervention on pain- and depression-acupoints would have specific efficacy and immune effects in patients with comorbid chronic pain and major depressive disorder (MDD). METHODS: We performed a subject- and assessor-blinded, crossover, and randomized controlled clinical trial of depression- and pain-specific acupuncture intervention and measured clinical responses and proinflammatory cytokines in patients with comorbid chronic pain and MDD. Specific acupoints for pain and depression were used in random order with a washout interval. Forty-seven patients were enrolled and randomly assigned to two groups: (1) the depression-pain group (23 patients who were treated with depression-specific acupoints and then the pain-specific acupoints after the washout) and (2) pain-depression group (24 patients with the reverse order). RESULTS: The pain-specific acupoints for pain did not reduce Brief Pain Inventory scores to a significantly greater degree (-0.97 ± 1.69) than the depression-specific acupoints (-0.28 ± 1.88); likewise, the depression-specific acupoints did not significantly ameliorate Hamilton Depression Rating Scale (-4.59 ± 6.02) than the pain-specific acupoints (-6.69 ± 6.61). The pain-specific acupoints improved Beck Depression Inventory-Second Edition (-6.74 ± 9.76) even better than the depression-specific acupoints (-1.92 ± 10.74). The depression-specific acupoints did not significantly decrease the depression-related interleukin (IL)-6 level (-1.24 ± 6.67) than the pain-specific acupoints (-0.60 ± 4.36). The changed levels of IL-1ß, tumor necrosis factor (TNF)-α between the depression-specific acupoints (-37.41 ± 194.49; -12.53 ± 54.68) and the pain-specific acupoints (-15.46 ± 87.56; -7.28 ± 27.86) could not reach significantly different, too. CONCLUSION: This study rejected our hypothesis that the pain-specific acupoints might produce superior analgesic effects than the depression-specific acupoints and vice versa. The cytokine results might imply that pain and depression share common biological mechanisms. (trial registration: https://www. CLINICALTRIALS: gov: NCT03328819).

Anti-Inflammatory Effect of Traditional Chinese Medicine on the Concept of Mind-Body Interface.

In this chapter, we conducted a systemic literature review for the anti-inflammatory effects of Traditional Chinese Medicine (TCM) applying molecular mechanisms focusing on the neuroinflammation and gut-brain axis in three neuropsychiatric disorders: major depressive disorder, Alzheimer's disease, and Parkinson's disease. We demonstrated the anti-inflammation or immunomodulation effects of TCM, including acupuncture, from basic and clinical research, including cellular and molecular approaches. In conclusion, inflammation plays a critical role in the neuropsychopathological process. At the same time, anti-inflammation seems to be the common biological pathway for the effects of TCM and acupuncture in depression, Alzheimer's disease, and Parkinson's disease.

Bilateral theta-burst stimulation on emotional processing in major depressive disorder: A functional neuroimaging study from a randomized, double-blind, sham-controlled trial.

AIM: Bilateral theta-burst stimulation (biTBS; intermittent TBS over the left dorsolateral prefrontal cortex [DLPFC] and continuous TBS over the right DLPFC) has demonstrated efficacy in improving symptoms in patients with major depressive disorder (MDD). However, the underlying brain mechanisms remain unknown. The authors aimed to investigate the antidepressant efficacy of biTBS monotherapy and its effects on the brain responses measured by functional magnetic resonance imaging (fMRI) during emotional processing in MDD. METHODS: The authors conducted a double-blind, randomized, sham-controlled trial of patients with MDD who exhibited no responses to at least one adequate antidepressant treatment for the prevailing episode. Recruited patients were randomly assigned to 10 biTBS monotherapy or sham stimulation sessions. The fMRI scans during performing emotional recognition task were obtained at baseline and after 10 sessions of treatment. Depressive symptoms were assessed using the 21-item Hamilton Rating Scale for Depression at baseline and the weeks 4, 8, 12, 16, 20, and 24 week. RESULTS: The biTBS group (n = 17) exhibited significant decreases in depression scores compared with the sham group (n = 11) at week 8 (70% vs 40%; P = 0.02), and the significant differences persisted during the 24-week follow-up periods. At week 4, when the treatment course was completed, patients in the biTBS group, but not in the sham group, exhibited increased brain activities over the left superior and middle frontal gyrus during negative emotional stimuli. CONCLUSION: The authors' findings provide the first evidence regarding the underlying neural mechanisms of biTBS therapy to improve clinical symptoms in patients with MDD.

Omega-3 fatty acids and blood-based biomarkers in Alzheimer's disease and mild cognitive impairment: A randomized placebo-controlled trial.

BACKGROUND: Increased serum levels of pro-inflammatory biomarkers are consistently associated with cognitive decline. The omega-3 unsaturated fatty acids (n-3 PUFAs) had been linked to slowing cognitive decline due to their potential anti-inflammatory effects. To our knowledge, the different regiments of pure DHA, pure EPA, and their combination on various associated symptoms of dementia, including a mild form of cognitive impairment (MCI) and Alzheimer's disease (AD), have never been studied. METHODS: This multisite, randomized, double-blind, placebo-controlled trial was conducted at two veteran's retirement centers and one medical center in central Taiwan between 2013 and 2015. 163 MCI or AD patients were randomly assigned to placebo (n = 40), docosahexaenoic acid (DHA, 0.7 g/day, n = 41), eicosapentaenoic acid (EPA, 1.6 g/day, n = 40), or EPA (0.8 g/day) + DHA (0.35 g/day) (n = 42) group for 24 months. The results were measured as the cognitive and functional abilities, biochemical, and inflammatory cytokines profiles. Chi-square tests, two-sample t-test, ANOVA, and linear mixedeffects models were conducted with p < 0.05. RESULTS: 131 (80%) participants had completed the trial with all cognitive, functional, and mood status assessments. The statistically significant difference between the placebo and treatment groups was not determined, concerning the changes in cognitive, functional, and mood status scores, the biochemical profiles, and inflammatory cytokines levels. However, EPA was found to reduce the C-C motif ligands 4 (CCL4) level (p < 0.001). Additionally, EPA could reduce the constructional praxis (p < 0.05) and spoken language ability scores (p < 0.01), and DHA also reduced the spoken language ability score (p < 0.05). CONCLUSION: Overall, n-3 PUFAs supplements did not reduce cognitive, functional, and depressive symptom outcomes, but spoken language ability and constructional praxis subitems of ADAS-cog. These findings show that attention to clinical heterogeneity in dementia is crucial when studying nutrients interventions, such as n-3 PUFAs. In addition, with small effect size CCL4 is a better indicator than other inflammatory cytokines for EPA treatment response.

Visual Cortex Alterations in Early and Late Blind Subjects During Tactile Perception.

Involvement of visual cortex varies during tactile perception tasks in early blind (EB) and late blind (LB) human subjects. This study explored differences in sensory motor networks associated with tactile task in EB and LB subjects and between children and adolescents. A total of 40 EB subjects, 40 LB subjects, and 30 sighted controls were recruited in two subgroups: children (6-12 years) and adolescents (13-19 years). Data were acquired using a 3T MR scanner. Analyses of blood oxygen level dependent (BOLD), functional connectivity (FC), correlation, and post hoc test for multiple comparisons were carried out. Difference in BOLD activity was observed in EB and LB groups in visual cortex during tactile perception, with increased FC of visual with dorsal attention and sensory motor networks in EB. EB adolescents exhibited increased connectivity with default mode and salience networks when compared with LB. Functional results correlated with duration of training, suggestive of better performance in EB. Alteration in sensory and visual networks in EB and LB correlated with duration of tactile training. Age of onset of blindness has an effect in cross-modal reorganization of visual cortex in EB and multimodal in LB in children and adolescents.

S-adenosyl-l-methionine (SAMe), cannabidiol (CBD), and kratom in psychiatric disorders: Clinical and mechanistic considerations.

Given the limitations of prescription antidepressants, many individuals have turned to natural remedies for the management of their mood disorders. We review three selected natural remedies that may be of potential use as treatments for depressive disorders and other psychiatric or neurological conditions. The best studied and best supported of these three remedies is S-adenosyl-l-methionine (SAMe), a methyl donor with a wide range of physiological functions in the human organism. With the increasing legalization of cannabis-related products, cannabidiol (CBD) has gained popularity for various potential indications and has even obtained approval in the United States and Canada for certain neurological conditions. Kratom, while potentially useful for certain individuals with psychiatric disorders, is perhaps the most controversial of the three remedies, in view of its greater potential for abuse and dependence. For each remedy, we will review indications, doses and delivery systems, potential anti-inflammatory and immunomodulatory action, adverse effects, and will provide recommendations for clinicians who may be considering prescribing these remedies in their practice.

Melatonergic agonist regulates circadian clock genes and peripheral inflammatory and neuroplasticity markers in patients with depression and anxiety.

OBJECTIVE: Circadian dysfunction is a core manifestation and a risk factor for psychiatric disorders. Ramelteon (RMT), a melatonin receptor agonist, has been shown to induce sleep phase shifts and has been used to normalize sleep onset time. RMT has been used in sleep disorders, depression and anxiety. In this study, we aimed to investigate the effects of RMT in regulating gene expression profiles of the circadian clock and peripheral markers of inflammation and neuroplasticity. METHODS: Sixteen patients with a diagnosis of primary insomnia comorbid with depression and anxiety and ten healthy controls were recruited in an 8-week open-label trial. The patients with primary insomnia received RMT 8 mg/day. The morning expression profiles of 15 core clock genes from peripheral blood mononuclear cells (PBMCs), urine and plasma levels of melatonin and its metabolite levels, and plasma inflammatory markers and neurotrophin levels were evaluated at baseline, 4th and 8th week of RMT treatment. RESULTS: RMT treatment was associated with significant clinical improvement in depression scores at 8th week (Hamilton depression rating scale scores (Mean ±â€¯SEM) from 21.5 ±â€¯2.44 to 14.31 ±â€¯2.25, p ≤ 0.05). The overall poor sleep quality (Pittsburgh sleep quality index) of the patient group significantly improved (p ≤ 0.05) following RMT treatment. The mRNA level analysis showed a significant association between RMT treatment and alterations of the nine core circadian genes (CLOCK, PER1, PER2, CRY1, CRY2, NR1D1, NR1D2, DEC1 and TIMELESS) in the patient group when compared with the control group (p ≤ 0.05). Compared with the controls, the patient group had a decrease in neurotrophins (brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and beta-nerve growth factor; p ≤ 0.05) but an increase in pro-inflammatory cytokine levels (interleukin-6, interleukin-1b, tumour necrosis factor-alpha and interferon gamma; p ≤ 0.05); RMT treatment normalized the levels of neurotrophins and cytokine levels. CONCLUSION: RMT treatment is able to restore phase-shifted melatonin markers, normalized the altered expression of the circadian genes, the levels of inflammatory cytokines and neurotrophins in patients with insomnia comorbid anxiety and depression.

Experimental alcoholism primes structural and functional impairment of the glymphatic pathway.

Alcoholism is a risk factor for the development of cognitive decline and dementia. Here we demonstrated that the glymphatic function in the brain was impaired by alcohol administration. Acute moderate alcohol administration substantially retarded and reduced the entry of subarachnoid cerebrospinal fluid (CSF) via the paravascular space into the cerebral parenchyma, thus impaired CSF-interstitial fluid (ISF) exchange and parenchymal amyloid ß (Aß) peptide clearance. The elevated release of ß-endorphin and reduced cerebrovascular pulsatility after acute alcohol administration may account for the impairment of the glymphatic function. Chronic moderate alcohol consumption led to pronounced activation of astrocytes and a widespread loss of perivascular AQP4 polarization in the brain, which results in an irreversible impairment of the glymphatic function. The results of the study suggest that impaired glymphatic functions and reduced parenchymal Aß clearance found in both acute and chronic alcohol treatment may contribute to the development of cognitive decline and dementia in alcoholism.

Omega-3 polyunsaturated fatty acids promote brain-to-blood clearance of ß-Amyloid in a mouse model with Alzheimer's disease.

Amyloid-ß (Aß) plaques is one of the typical pathological hallmark of Alzheimer disease (AD). Accumulating evidence suggests that the imbalance between Aß production and clearance leads to extracellular Aß accumulation in the brain. It is reported that the blood-brain barrier (BBB) transport plays a predominant role in Aß clearance from brain to blood. In the present study, we investigated dynamic alterations of BBB transport function in the early disease stage of AD using APPswe/PS1dE9 C57BL/6J (APP/PS1) transgenic mice. Our results showed that the expression of lipoprotein receptor-related protein 1 (LRP-1), a main efflux transporter of BBB, started to decrease at the age of 4 months old. Interestingly, supplementing with fish oil which is rich in omega-3 polyunsaturated fatty acids (PUFAs) significantly enhanced the expression level of LRP-1 and promoted Aß clearance from the bran to circulation, as revealed by reduced soluble/insoluble Aß levels and senile plaques in the brain parenchyma and a corresponding increase of Aß levels in plasma. Besides, fish oil supplement significantly inhibited the NF-κB activation, reduced the expression of interleukin-1ß and tumor necrosis factor-α, and suppressed the glial activation in APP/PS1 mice. The results of the study provide evidence that BBB transport function could be impaired at a very early disease stage, which might contribute to Aß pathological accumulation in AD, and omega-3 PUFAs intervention could be an effective strategy for the prevention of the progression of AD through promoting Aß clearance from brain-to-blood.

miR-200a-3p modulates gene expression in comorbid pain and depression: Molecular implication for central sensitization.

Chronic pain and depression are often comorbid exhibiting common clinical presentations and biological connections related to central nervous system sensitization. Epigenetic regulation of gene expression in the brain plays a crucial role in response to long-lasting stress and chronic pain, and microRNA imbalance in the prefrontal cortex (PFC) might be involved in central sensitization. Male Sprague Dawley rats were subjected to unpredictable chronic mild stress (UCMS) and spared nerve injury (SNI) to initiate depressive-like behavior and chronic pain behavior, respectively. The next-generation sequencing technique was employed to analyze PFC microRNAs in both the UCMS and SNI models. Rats exposed to either UCMS or SNI exhibited both depressive-like and chronic pain behaviors. Five specific microRNAs (miR-10a-5p, miR-182, miR-200a-3p, miR-200b-3p, and miR-429) were simultaneously down-regulated in the depressive-like and chronic pain models after 4 weeks of short-term stress. Gene ontology revealed that the 4-week period of stress enhanced neurogenesis. Only the miR-200a-3p level was continuously elevated under prolonged stress, suggesting roles of reduced neurogenesis, inflammatory activation, disturbed circadian rhythm, lipid metabolism, and insulin secretion in the co-existence of pain and depression. Thus we conclude that miR-200a-3p might be a specific biomarker of central sensitization in chronic pain and depression.

Clinical Efficacy and Biological Regulations of ω-3 PUFA-Derived Endocannabinoids in Major Depressive Disorder.

BACKGROUND: Endocannabinoids (ECs) are one type of bioactive endogenous neuroinflammatory mediator derived from polyunsaturated fatty acids (PUFAs), which may regulate the emotional processes. Here, we assessed the effect of ω-3 PUFAs on EC levels, which may be the novel targets for the ω-3 PUFAs' antidepressive effects. METHODS: We conducted a 12-week double-blind, nonplacebo, randomized controlled trial. Eighty-eight major depressive disorder (MDD) participants were randomly assigned to receive eicosapentaenoic acid (EPA, 3.0 g/day), docosahexaenoic acid (DHA, 1.4 g/day), or a combination of EPA (1.5 g/d) and DHA (0.7 g/day). Eighty-five participants completed the trial, and their clinical remission and plasma PUFA-derived EC levels (pmol/mL) were measured. RESULTS: The cumulative rates of clinical remission were significantly higher in the EPA and EPA + DHA groups than the DHA group (51.85 and 53.84 vs. 34.37%; p =0.027 and p =0.024, respectively). EPA and EPA + DHA treatments increased the eicosapentaenoylethanolamide (EPEA) levels compared to DHA treatment (0.33 ± 0.18 and 0.35 ± 0.24 vs. 0.08 ± 0.12; p =0.002 and p =0.001, respectively), while EPA + DHA treatment increased the docosahexaenoylethanolamide levels more than EPA treatment (1.34 ± 2.09 vs. 0.01 ± 1.79; p =0.006). Plasma EPEA levels were positively correlated with rates of clinical remission (hazard ratio: 1.60, 95% confidence interval: 1.08-2.39). CONCLUSIONS: Treatments enriched with EPA increased plasma EPEA levels, which was positively associated with clinical remission. This finding may suggest that levels of plasma EPEA play a potential novel endogenous therapeutic target in MDD.

A limited evaluation of the association of race and anesthetic medication administration: A single-center experience with appendectomies.

BACKGROUND: Although it is known that a patient's race may influence their medical care, racial patterns of medication administration in pediatric anesthesia have not been well-studied. The aim of this study was to determine if differences exist between Black and White children with regard to administration of anesthetic and analgesic medications for a single procedure at our institution. METHODS: We conducted a retrospective review of medications administered to patients for emergency appendectomies at a large academic children's hospital from 2010 to 2015. We examined the association between patient race and administration of preoperative midazolam and intraoperative ondansetron, lidocaine, ketorolac, and weight-based doses of fentanyl and morphine. RESULTS: During the study period, 1680 patients (1329 White, 351 Black) underwent emergency appendectomy. There were no significant racial differences in administration of intraoperative anesthetic medications between Black and White children. In unadjusted analysis, Black children were less likely to receive preoperative midazolam than White children (OR=0.74 [95% CI, 0.58-0.94], P=.012). After adjusting for confounders, there was no evidence of racial differences in administration of preoperative or intraoperative medications. CONCLUSION: We did not find a significant difference in preoperative or intraoperative medication administration based on race when we adjusted for age, gender, and attending anesthesiologist practice patterns. We encourage all institutions to monitor their own practice patterns with regard to race.

Exploration of Voids, Acoustic Properties and Vibration Damping Ratio of Cyperus Pangorei Rottb Fiber and Ramie Fiber Reinforced with Epoxy Resin Hybrid Composites.

Noise pollution is a major threat to the health and well-being of the entire world; this issue forces researchers to find new sound absorption and insulating material. In this paper, the sound absorption coefficient and vibration damping factor of panels manufactured from Cyperus pangorei rottb and ramie fiber reinforced with epoxy resin are explored. Cyperus pangorei rottb grass fiber and ramie fiber are widely available natural fibers. Cyperus pangorei rottb grass fiber is used in mat manufacturing, whereas ramie is widely used as a fabric. Using both of these fibers, six variant panels using a vacuum resin infusion process (VRIP) were fabricated. The panels were named C, R, CR, RCR-Flat, RCR-Curved, and RCR-Perforated. All the panels were tested for the sound absorption coefficient using an impedance tube with a frequency ranging up to 6300 Hz. Modal analysis was carried out by using the impulse hammer excitation method. A micro X-ray computed tomography (CT) scan was used to study the voids present in the panels. The results were compared among the six variants. The results show that the RCR-curved panel had the highest sound-absorbing coefficient of 0.976 at a frequency range between 4500 Hz to 5000 Hz. These panels also showed better natural frequency and damping factors. The presence of internal voids in these panels enhances sound absorption properties. These panels can be used at higher frequencies.

Gray Matter Atrophy in a 6-OHDA-induced Model of Parkinson's Disease.

INTRODUCTION: Magnetic resonance imaging (MRI) based brain morphometric changes in unilateral 6-hydroxydopamine (6-OHDA) induced Parkinson's disease (PD) model can be elucidated using voxel-based morphometry (VBM), study of alterations in gray matter volume and Machine Learning (ML) based analyses. METHODS: We investigated gray matter atrophy in 6-OHDA induced PD model as compared to sham control using statistical and ML based analysis. VBM and atlas-based volumetric analysis was carried out at regional level. Support vector machine (SVM)-based algorithms wherein features (volume) extracted from (a) each of the 150 brain regions (b) statistically significant features (only) and (c) volumes of each cluster identified after application of VBM (VBM_Vol) were used for training the decision model. The lesion of the 6-OHDA model was validated by estimating the net contralateral rotational behaviour by the injection of apomorphine drug and motor impairment was assessed by rotarod and open field test. RESULTS AND DISCUSSION: In PD, gray matter volume (GMV) atrophy was noted in bilateral cortical and subcortical brain regions, especially in the internal capsule, substantia nigra, midbrain, primary motor cortex and basal ganglia-thalamocortical circuits in comparison with sham control. Behavioural results revealed an impairment in motor performance. SVM analysis showed 100% classification accuracy, sensitivity and specificity at both 3 and 7 weeks using VBM_Vol. CONCLUSION: Unilateral 6-OHDA induced GMV changes in both hemispheres at 7th week may be associated with progression of the disease in the PD model. SVM based approaches provide an increased classification accuracy to elucidate GMV atrophy.

Drug Screening and Validation Targeting TDP-43 Proteinopathy for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) stands as a rare, yet severely debilitating disorder marked by the deterioration of motor neurons (MNs) within the brain and spinal cord, which is accompanied by degenerated corticobulbar/corticospinal tracts and denervation in skeletal muscles. Despite ongoing research efforts, ALS remains incurable, attributed to its intricate pathogenic mechanisms. A notable feature in the pathology of ALS is the prevalence of TAR DNA-binding protein 43 (TDP-43) proteinopathy, detected in approximately 97% of ALS cases, underscoring its significance in the disease's progression. As a result, strategies targeting the aberrant TDP-43 protein have garnered attention as a potential avenue for ALS therapy. This review delves into the existing drug screening systems aimed at TDP-43 proteinopathy and the models employed for drug efficacy validation. It also explores the hurdles encountered in the quest to develop potent medications against TDP-43 proteinopathy, offering insights into the intricacies of drug discovery and development for ALS. Through this comprehensive analysis, the review sheds light on the critical aspects of identifying and advancing therapeutic solutions for ALS.