C. elegans: a prominent platform for modeling and drug screening in neurological disorders.

INTRODUCTION: Human neurodevelopmental and neurodegenerative diseases (NDevDs and NDegDs, respectively) encompass a broad spectrum of disorders affecting the nervous system with an increasing incidence. In this context, the nematode C. elegans, has emerged as a benchmark model for biological research, especially in the field of neuroscience. AREAS COVERED: The authors highlight the numerous advantages of this tiny worm as a model for exploring nervous system pathologies and as a platform for drug discovery. There is a particular focus given to describing the existing models of C. elegans for the study of NDevDs and NDegDs. Specifically, the authors underscore their strong applicability in preclinical drug development. Furthermore, they place particular emphasis on detailing the common techniques employed to explore the nervous system in both healthy and diseased states. EXPERT OPINION: Drug discovery constitutes a long and expensive process. The incorporation of invertebrate models, such as C. elegans, stands as an exemplary strategy for mitigating costs and expediting timelines. The utilization of C. elegans as a platform to replicate nervous system pathologies and conduct high-throughput automated assays in the initial phases of drug discovery is pivotal for rendering therapeutic options more attainable and cost-effective.

Circadian disruption and human health.

Circadian disruption is pervasive and can occur at multiple organizational levels, contributing to poor health outcomes at individual and population levels. Evidence points to a bidirectional relationship, in that circadian disruption increases disease severity and many diseases can disrupt circadian rhythms. Importantly, circadian disruption can increase the risk for the expression and development of neurologic, psychiatric, cardiometabolic, and immune disorders. Thus, harnessing the rich findings from preclinical and translational research in circadian biology to enhance health via circadian-based approaches represents a unique opportunity for personalized/precision medicine and overall societal well-being. In this Review, we discuss the implications of circadian disruption for human health using a bench-to-bedside approach. Evidence from preclinical and translational science is applied to a clinical and population-based approach. Given the broad implications of circadian regulation for human health, this Review focuses its discussion on selected examples in neurologic, psychiatric, metabolic, cardiovascular, allergic, and immunologic disorders that highlight the interrelatedness between circadian disruption and human disease and the potential of circadian-based interventions, such as bright light therapy and exogenous melatonin, as well as chronotherapy to improve and/or modify disease outcomes.

Coenzyme Q10 a mitochondrial restorer for various brain disorders.

Coenzyme Q10 (ubiquinone or CoQ10) is a lipid molecule that acts as an electron mobile carrier of the electron transport chain and also contains antioxidant properties. Supplementation of CoQ10 has been very useful to treat mitochondrial diseases. CoQ10 along with its synthetic analogue, idebenone, is used largely to treat various neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, and Friedreich's ataxia and additional brain disease condition like autism, multiple sclerosis, epilepsy, depression, and bipolar disorder, which are related to mitochondrial impairment. In this article, we have reviewed numerous physiological functions of CoQ10 and the rationale for its use in clinical practice in different brain disorders.

Sphingolipid metabolism governs Purkinje cell patterned degeneration in Atxn1[82Q]/+ mice.

Patterned degeneration of Purkinje cells (PCs) can be observed in a wide range of neuropathologies, but mechanisms behind nonrandom cerebellar neurodegeneration remain unclear. Sphingolipid metabolism dyshomeostasis typically leads to PC neurodegeneration; hence, we questioned whether local sphingolipid balance underlies regional sensitivity to pathological insults. Here, we investigated the regional compartmentalization of sphingolipids and their related enzymes in the cerebellar cortex in healthy and pathological conditions. Analysis in wild-type animals revealed higher sphingosine kinase 1 (Sphk1) levels in the flocculonodular cerebellum, while sphingosine-1-phosphate (S1P) levels were higher in the anterior cerebellum. Next, we investigated a model for spinocerebellar ataxia type 1 (SCA1) driven by the transgenic expression of the expanded Ataxin 1 protein with 82 glutamine (82Q), exhibiting severe PC degeneration in the anterior cerebellum while the flocculonodular region is preserved. In Atxn1[82Q]/+ mice, we found that levels of Sphk1 and Sphk2 were region-specific decreased and S1P levels increased, particularly in the anterior cerebellum. To determine if there is a causal link between sphingolipid levels and neurodegeneration, we deleted the Sphk1 gene in Atxn1[82Q]/+ mice. Analysis of Atxn1[82Q]/+; Sphk1-/- mice confirmed a neuroprotective effect, rescuing a subset of PCs in the anterior cerebellum, in domains reminiscent of the modules defined by AldolaseC expression. Finally, we showed that Sphk1 deletion acts on the ATXN1[82Q] protein expression and prevents PC degeneration. Taken together, our results demonstrate that there are regional differences in sphingolipid metabolism and that this metabolism is directly involved in PC degeneration in Atxn1[82Q]/+ mice.

Emerging Benefits: Pathophysiological Functions and Target Drugs of the Sigma-1 Receptor in Neurodegenerative Diseases.

The sigma-1 receptor (Sig-1R) is encoded by the SIGMAR1 gene and is a nonopioid transmembrane receptor located in the mitochondrial-associated endoplasmic reticulum membrane (MAM). It helps to locate endoplasmic reticulum calcium channels, regulates calcium homeostasis, and acts as a molecular chaperone to control cell fate and participate in signal transduction. It plays an important role in protecting neurons through a variety of signaling pathways and participates in the regulation of cognition and motor behavior closely related to neurodegenerative diseases. Based on its neuroprotective effects, Sig-1R has now become a breakthrough target for alleviating Alzheimer's disease and other neurodegenerative diseases. This article reviews the most cutting-edge research on the function of Sig-1R under normal or pathologic conditions and target drugs of the sigma-1 receptor in neurodegenerative diseases.

Significant Impact of Coffee Consumption on MR-Based Measures of Cardiac Function in a Population-Based Cohort Study without Manifest Cardiovascular Disease.

Subclinical effects of coffee consumption (CC) with regard to metabolic, cardiac, and neurological complications were evaluated using a whole-body magnetic resonance imaging (MRI) protocol. A blended approach was used to estimate habitual CC in a population-based study cohort without a history of cardiovascular disease. Associations of CC with MRI markers of gray matter volume, white matter hyperintensities, cerebral microhemorrhages, total and visceral adipose tissue (VAT), hepatic proton density fat fraction, early/late diastolic filling rate, end-diastolic/-systolic and stroke volume, ejection fraction, peak ejection rate, and myocardial mass were evaluated by linear regression. In our analysis with 132 women and 168 men, CC was positively associated with MR-based cardiac function parameters including late diastolic filling rate, stroke volume (p < 0.01 each), and ejection fraction (p < 0.05) when adjusting for age, sex, smoking, hypertension, diabetes, Low-density lipoprotein (LDL), triglycerides, cholesterol, and alcohol consumption. CC was inversely associated with VAT independent of demographic variables and cardiovascular risk factors (p < 0.05), but this association did not remain significant after additional adjustment for alcohol consumption. CC was not significantly associated with potential neurodegeneration. We found a significant positive and independent association between CC and MRI-based systolic and diastolic cardiac function. CC was also inversely associated with VAT but not independent of alcohol consumption.

Circadian Rhythm Sleep-Wake Disorders: a Contemporary Review of Neurobiology, Treatment, and Dysregulation in Neurodegenerative Disease.

Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light-dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep-wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep-wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders - Third Edition, including jet lag and shift work disorders, delayed and advanced sleep-wake phase rhythm disorders, non-24-h sleep-wake rhythm disorder, and irregular sleep-wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.

The Emerging Role of Neuronal Organoid Models in Drug Discovery: Potential Applications and Hurdles to Implementation.

The high failure rate of drugs in the clinical pipeline is likely in part the result of inadequate preclinical models, particularly those for neurologic disorders and neurodegenerative disease. Such preclinical animal models often suffer from fundamental species differences and rarely recapitulate all facets of neurologic conditions, whereas conventional two-dimensional (2D) in vitro models fail to capture the three-dimensional spatial organization and cell-to-cell interactions of brain tissue that are presumed to be critical to the function of the central nervous system. Recent studies have suggested that stem cell-derived neuronal organoids are more physiologically relevant than 2D neuronal cultures because of their cytoarchitecture, electrophysiological properties, human origin, and gene expression. Hence there is interest in incorporating such physiologically relevant models into compound screening and lead optimization efforts within drug discovery. However, despite their perceived relevance, compared with previously used preclinical models, little is known regarding their predictive value. In fact, some have been wary to broadly adopt organoid technology for drug discovery because of the low-throughput and tedious generation protocols, inherent variability, and lack of compatible moderate-to-high-throughput screening assays. Consequently, microfluidic platforms, specialized bioreactors, and automated assays have been and are being developed to address these deficits. This mini review provides an overview of the gaps to broader implementation of neuronal organoids in a drug discovery setting as well as emerging technologies that may better enable their utilization. SIGNIFICANCE STATEMENT: Neuronal organoid models offer the potential for a more physiological system in which to study neurological diseases, and efforts are being made to employ them not only in mechanistic studies but also in profiling/screening purposes within drug discovery. In addition to exploring the utility of neuronal organoid models within this context, efforts in the field aim to standardize such models for consistency and adaptation to screening platforms for throughput evaluation. This review covers potential impact of and hurdles to implementation.

Cardiac electrical remodeling and neurodegenerative diseases association.

Cardiac impairment contributes significantly to the mortality associated with several neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), primarily recognized as brain pathologies. These diseases may be caused by aggregation of a misfolded protein, most often, in the brain, although new evidence also reveals peripheral abnormalities. After characterization of the cardiac involvement in neurodegenerative diseases, several studies concentrated on elucidating the cause of the impaired cardiac function. However, most of the current knowledge is focused on the mechanical aspects of the heart rather than the electrical disturbances. The main objective of this review is to summarize the most recent advances in the elucidation of cardiac electrical remodeling in the neurodegenerative environment. We aimed to determine a crosstalk between the heart and the brain in three neurodegenerative conditions: AD, PD, and HD. We found that the most studies demonstrated important alterations in the electrocardiogram (ECG) of patients with neurodegeneration and in animal models of the conditions. We also showed that little is described when considering excitability disruptions in cardiomyocytes, for example, action potential impairments. It is a matter of contention whether central nervous system abnormalities or the peripheral ones increase the risk of heart diseases in patients with neurodegenerative conditions. To determine this notion, there is a need for new heart studies focusing specifically on the cardiac electrophysiology (e.g., ECG and cardiomyocyte excitability). This review could serve as an important guide in designing novel accurate approaches targeting the heart in neuronal conditions.

Structured form of DHA prevents neurodegenerative disorders: A better insight into the pathophysiology and the mechanism of DHA transport to the brain.

Docosahexaenoic acid (DHA) is one of the most important fatty acids that plays a critical role in maintaining proper brain function and cognitive development. Deficiency of DHA leads to several neurodegenerative disorders and, therefore, dietary supplementations of these fatty acids are essential to maintain cognitive health. However, the complete picture of how DHA is incorporated into the brain is yet to be explored. In general, the de novo synthesis of DHA is poor, and targeting the brain with specific phospholipid carriers provides novel insights into the process of reduction of disease progression. Recent studies have suggested that compared to triacylglycerol form of DHA, esterified form of DHA (i.e., lysophosphatidylcholine [lysoPC]) is better incorporated into the brain. Free DHA is transported across the outer membrane leaflet of the blood-brain barrier via APOE4 receptors, whereas DHA-lysoPC is transported across the inner membrane leaflet of the blood-brain barrier via a specific protein called Mfsd2a. Dietary supplementation of this lysoPC specific form of DHA is a novel therapy and is used to decrease the risk of various neurodegenerative disorders. Currently, structured glycerides of DHA - novel nutraceutical agents - are being widely used for the prevention and treatment of various neurological diseases. However, it is important to fully understand their metabolic regulation and mechanism of transportation to the brain. This article comprehensively reviews various studies that have evaluated the bioavailability of DHA, mechanisms of DHA transport, and role of DHA in preventing neurodegenerative disorders, which provides better insight into the pathophysiology of these disorders and use of structured DHA in improving neurological health.

Preclinical and Clinical Evidence for the Involvement of Sphingosine 1-Phosphate Signaling in the Pathophysiology of Vascular Cognitive Impairment.

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P1-S1P5. Scrutiny of S1P-regulated pathways over the past three decades has identified important and occasionally counteracting functions in the brain and cerebrovascular system. For example, while S1P1 and S1P3 mediate proinflammatory effects on glial cells and directly promote endothelial cell barrier integrity, S1P2 is anti-inflammatory but disrupts barrier integrity. Cumulatively, there is significant preclinical evidence implicating critical roles for this pathway in regulating processes that drive cerebrovascular disease and vascular dementia, both being part of the continuum of vascular cognitive impairment (VCI). This is supported by clinical studies that have identified correlations between alterations of S1P and cognitive deficits. We review studies which proposed and evaluated potential mechanisms by which such alterations contribute to pathological S1P signaling that leads to VCI-associated chronic neuroinflammation and neurodegeneration. Notably, S1P receptors have divergent but overlapping expression patterns and demonstrate complex interactions. Therefore, the net effect produced by S1P represents the cumulative contributions of S1P receptors acting additively, synergistically, or antagonistically on the neural, vascular, and immune cells of the brain. Ultimately, an optimized therapeutic strategy that targets S1P signaling will have to consider these complex interactions.

Thiamine Pyrophosphokinase Deficiency due to Mutations in the TPK1 Gene: A Rare, Treatable Neurodegenerative Disorder.

TPK deficiency due to TPK1 mutations is a rare neurodegenerative disorder, also known as thiamine metabolism dysfunction syndrome 5 (OMIM no.: 614458). Here, we report a new patient with compound heterozygous TPK1 mutations, of which one has not been described so far. The individual reported here suffered from acute onset encephalopathy, ataxia, muscle hypotonia, and regression of developmental milestones in early infancy, repeatedly triggered by febrile infections. Initiation of high-dose thiamine and magnesium supplementation led to a marked and sustained improvement of alertness, ataxia, and muscle tone within days. Contrary to the described natural history of patients with TPK deficiency, the disease course was favorable under thiamine treatment without deterioration or developmental regression during the follow-up period. TPK deficiency is a severe neurodegenerative disease. This case report demonstrates that this condition is potentially treatable. High-dose thiamine treatment should therefore be initiated immediately after diagnosis or even upon suspicion.

Evaluating and modulating TFEB in the control of autophagy: toward new treatments in CNS disorders.

TFEB is a mammalian transcription factor that binds directly to the CLEAR consensus sequence (5'-GTCACGTGAC-3') present in the regulatory regions of genes inducing autophagosome formation, autophagosome-lysosome fusion, hydrolase enzyme expression, and lysosomal exocytosis. By modulating these activities, TFEB coordinates on-demand control over each cell's degradation pathway. Thus, a nuclear signaling pathway regulates cellular energy metabolism through TFEB. Our growing understanding of the role of TFEB and CLEAR in the promotion of healthy clearance together with in vitro and in vivo preclinical findings in various animal models of disease supports the conclusion that the pharmacological activation of TFEB could clear toxic proteins to treat both rare and common forms of neurodegenerative disease.

Applications of Acupuncture Therapy in Modulating the Plasticity of Neurodegenerative Disease and Depression: Do MicroRNA and Neurotrophin BDNF Shed Light on the Underlying Mechanism?

As the global population ages, the incidence of neurodegenerative diseases has risen. Furthermore, it has been suggested that depression, especially in elderly people, may also be an indication of latent neurodegeneration. Stroke, Alzheimer's disease (AD), and Parkinson's disease (PD) are usually accompanied by depression. The urgent challenge is further enforced by psychiatric comorbid conditions, particularly the feeling of despair in these patients. Fortunately, as our understanding of the neurobiological substrates of maladies affecting the central nervous system (CNS) has increased, more therapeutic options and novel potential biological mechanisms have been presented: (1) Neurodegenerative diseases share some similarities in their pathological characteristics, including changes in neuron structure or function and neuronal plasticity. (2) MicroRNAs (miRNAs) are small noncoding RNAs that contribute to the pathogenesis of diverse neurological disease. (3) One ubiquitous neurotrophin, brain-derived neurotrophic factor (BDNF), is crucial for the development of the nervous system. Accumulating data have indicated that miRNAs not only are related to BDNF regulation but also can directly bind with the 3'-UTR of BDNF to regulate BDNF and participate in neuroplasticity. In this short review, we present evidence of shared biological substrates among stroke, AD, PD, and depression and summarize the possible influencing mechanisms of acupuncture on the neuroplasticity of these diseases. We discuss neuroplasticity underscored by the roles of miRNAs and BDNF, which might further reveal the potential biological mechanism of neurodegenerative diseases and depression by acupuncture.

Preclinical models of disease and multimorbidity with focus upon cardiovascular disease and dementia.

The use of animal models is fundamental to furthering our understanding of human disease mechanisms, as well as identifying potential therapeutic targets. Diseases of ageing often involve multiple body systems; however, multi-systemic features are not fully recapitulated in the many of the animal models available. Therefore, combining pre-clinical models to better reflect the multimorbidities observed at the clinical level is critical. This review will highlight some of the key pre-clinical experimental models associated with cardiovascular (atherosclerosis, coronary heart disease), cerebrovascular (stroke, vascular dementia), metabolic (obesity, type-2 diabetes mellitus) and neurological (amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's, epilepsy) diseases, and whether these models encompass known multimorbidities. In addition to this, we discuss established pre-clinical models that combine two or more conditions, within the context of dementia.

Interaction between Tea Polyphenols and Intestinal Microbiota in Host Metabolic Diseases from the Perspective of the Gut-Brain Axis.

Tea polyphenols (TP) have shown multiple biological activities and the ability to modulate the composition and function of intestinal microbiota. Certain human metabolic diseases are engendered by the disruption of the circadian rhythm. Circadian rhythm oscillations exist in both intestinal microbiota and hypothalamus. The brain-gut-microbiome axis enables intestinal microorganisms to communicate with the brain. The close reciprocity between intestinal microbiota and circadian rhythm supplies a new opportunity for TP to regulate circadian-rhythm-related diseases relying on intestinal microbiota. Therefore, based on the potential bidirectional association of the brain and gut microbes, this review mainly discussed the interaction between TP and intestinal microbiota from the perspective of the gut-brain axis (GBA) to improve the theory of metabolic diseases prevention.

Pentacyclic triterpenoid-rich fraction of the Hardy kiwi (Actinidia arguta) improves brain dysfunction in high fat diet-induced obese mice.

This study was performed to investigate the effect of the chloroform fraction from Actinidia arguta (CFAA) on cognitive dysfunction in a C57BL/6 mouse model fed a high-fat diet (HFD) for 12 weeks. The CFAA has the protective effect on high glucose-induced neurotoxicity in MC-IXC cell (neuroblastoma cell line). In a C57BL/6 mouse model fed a HFD for 12 weeks, the improved glucose tolerance and cognitive dysfunction were observed in a group ingesting CFAA. In the brain tissue analysis, the impaired cholinergic, antioxidant system and mitochondria functions were improved in the CFAA group. In addition, in a molecular biology study, it was observed that CFAA improves HFD-induced abnormal insulin signaling such as increase of IRS phosphorylation at serine residues and reduction of Akt phosphorylation caused by the increase of JNK phosphorylation and then inhibited apoptosis. In the UPLC Q-TOF/MS analysis, pentacyclic triterpenoids such as asiatic acid (AA), madecassic acid (MA) were identified in CFAA as main compounds. Therefore, these results propose that Actinidia arguta rich in pentacyclic triterpenoids may be effective as preventive matter a therapeutic strategy to improve neurodegenerative disease caused by HFD.

Deletion of Topoisomerase 1 in excitatory neurons causes genomic instability and early onset neurodegeneration.

Topoisomerase 1 (TOP1) relieves torsional stress in DNA during transcription and facilitates the expression of long (>100 kb) genes, many of which are important for neuronal functions. To evaluate how loss of Top1 affected neurons in vivo, we conditionally deleted (cKO) Top1 in postmitotic excitatory neurons in the mouse cerebral cortex and hippocampus. Top1 cKO neurons develop properly, but then show biased transcriptional downregulation of long genes, signs of DNA damage, neuroinflammation, increased poly(ADP-ribose) polymerase-1 (PARP1) activity, single-cell somatic mutations, and ultimately degeneration. Supplementation of nicotinamide adenine dinucleotide (NAD+) with nicotinamide riboside partially blocked neurodegeneration, and increased the lifespan of Top1 cKO mice by 30%. A reduction of p53 also partially rescued cortical neuron loss. While neurodegeneration was partially rescued, behavioral decline was not prevented. These data indicate that reducing neuronal loss is not sufficient to limit behavioral decline when TOP1 function is disrupted.

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.