Pharmacological and Non-pharmacological Approaches for the Management of Neuropathic Pain in Multiple Sclerosis.

Multiple sclerosis is a chronic inflammatory disease that affects the central nervous system and can cause various types of pain including ongoing extremity pain, Lhermitte's phenomenon, trigeminal neuralgia, and mixed pain. Neuropathic pain is a major concern for individuals with multiple sclerosis as it is directly linked to myelin damage in the central nervous system and the management of neuropathic pain in multiple sclerosis is challenging as the options available have limited efficacy and can cause unpleasant side effects. The literature search was conducted across two databases, PubMed, and Google Scholar. Eligible studies included clinical trials, observational studies, meta-analyses, systematic reviews, and narrative reviews. The objective of this article is to provide an overview of literature on pharmacological and non-pharmacological strategies employed in the management of neuropathic pain in multiple sclerosis. Pharmacological options include cannabinoids, muscle relaxants (tizanidine, baclofen, dantrolene), anticonvulsants (benzodiazepines, gabapentin, phenytoin, carbamazepine, lamotrigine), antidepressants (duloxetine, venlafaxine, tricyclic antidepressants), opioids (naltrexone), and botulinum toxin variants, which have evidence from various clinical trials. Non-pharmacological approaches for trigeminal neuralgia may include neurosurgical methods. Non-invasive methods, physical therapy, and psychotherapy (cognitive behavioral therapy, acceptance and commitment therapy and mindfulness-based stress reduction) may be recommended for patients with neuropathic pain in multiple sclerosis. The choice of treatment depends on the severity and type of pain as well as other factors, such as patient preferences and comorbidities. There is a pressing need for healthcare professionals and researchers to prioritize the development of better strategies for managing multiple sclerosis-induced neuropathic pain.

Hereditary spastic paraplegia: Novel insights into the pathogenesis and management.

Hereditary spastic paraplegia is a genetically heterogeneous neurodegenerative disorder characterised primarily by muscle stiffness in the lower limbs. Neurodegenerative disorders are conditions that result from cellular and metabolic abnormalities, many of which have strong genetic ties. While ageing is a known contributor to these changes, certain neurodegenerative disorders can manifest early in life, progressively affecting a person's quality of life. Hereditary spastic paraplegia is one such condition that can appear in individuals of any age. In hereditary spastic paraplegia, a distinctive feature is the degeneration of long nerve fibres in the corticospinal tract of the lower limbs. This degeneration is linked to various cellular and metabolic processes, including mitochondrial dysfunction, remodelling of the endoplasmic reticulum membrane, autophagy, abnormal myelination processes and alterations in lipid metabolism. Additionally, hereditary spastic paraplegia affects processes like endosome membrane trafficking, oxidative stress and mitochondrial DNA polymorphisms. Disease-causing genetic loci and associated genes influence the progression and severity of hereditary spastic paraplegia, potentially affecting various cellular and metabolic functions. Although hereditary spastic paraplegia does not reduce a person's lifespan, it significantly impairs their quality of life as they age, particularly with more severe symptoms. Regrettably, there are currently no treatments available to halt or reverse the pathological progression of hereditary spastic paraplegia. This review aims to explore the metabolic mechanisms underlying the pathophysiology of hereditary spastic paraplegia, emphasising the interactions of various genes identified in recent network studies. By comprehending these associations, targeted molecular therapies that address these biochemical processes can be developed to enhance treatment strategies for hereditary spastic paraplegia and guide clinical practice effectively.

Serum Level of Brain-Derived Neurotrophic Factor and Thrombotic Type Are Predictive of Cognitive Impairment in the Acute Period of Ischemic Strokes Patients.

40-70% of patients after a stroke, including a mild one, may experience cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays a significant role in the pathogenesis and rehabilitation of ischemic stroke and also affects the patients' recovery prognosis. An association between cognitive impairment in the poststroke period and lower peripheral BDNF levels is known, but the prognostic significance of serum BDNF levels and clinical characteristics for the risk of developing cognitive impairment in the acute period remains uncertain. We conducted a prospective cohort study of patients in the acute phase of ischemic stroke. Clinical examination, assessment of neurological status, neuropsychological testing, and laboratory analyzes were performed on patients at 1 and 14 days after ischemic stroke. The state of cognitive functions was assessed by the Mini-Mental State Examination scale. Quantification of BDNF in blood serum was performed by solid-phaseenzyme-linked immunosorbent assay (ELISA). We found that within 14 days after an acute ischemic stroke, we found a decrease in the clinical severity of patients compared to 1 day of the onset of the disease before the start of treatment and a significant decrease in the level of BDNF in the blood serum of patients with ischemic stroke both on the first and on the 14th day. However, during the 2 weeks of the acute period, no significant changes were detected, despite the general improvement of the clinical condition. In our study, cognitive impairment was found in almost half of the patients on the first day of ischemic stroke, and there was no significant reduction in this prevalence over 2 weeks. We found that a low level of BDNF and a thrombotic subtype of ischemic stroke can be risk factors for cognitive impairment in the acute period, which can be useful in planning treatment and rehabilitation measures.

Immunological and inflammatory effects of infectious diseases in circadian rhythm disruption and future therapeutic directions.

BACKGROUND: Circadian rhythm is characterised by daily variations in biological activity to align with the light and dark cycle. These diurnal variations, in turn, influence physiological functions such as blood pressure, temperature, and sleep-wake cycle. Though it is well established that the circadian pathway is linked to pro-inflammatory responses and circulating immune cells, its association with infectious diseases is widely unknown. OBJECTIVE: This comprehensive review aims to describe the association between circadian rhythm and host immune response to various kinds of infection. METHODS: We conducted a literature search in databases Pubmed/Medline and Science direct. Our paper includes a comprehensive analysis of findings from articles in English which was related to our hypothesis. FINDINGS: Molecular clocks determine circadian rhythm disruption in response to infection, influencing the host's response toward infection. Moreover, there is a complex interplay with intrinsic oscillators of pathogens and the influence of specific infectious processes on the CLOCK: BMAL1 pathway. Such mechanisms vary for bacterial and viral infections, both well studied in the literature. However, less is known about the association of parasitic infections and fungal pathogens with circadian rhythm modulation. CONCLUSION: It is shown that bidirectional relationships exist between circadian rhythm disruption and infectious process, which contains interplay between the host's and pathogens' circadian oscillator, immune response, and the influence of specific infectious. Further studies exploring the modulations of circadian rhythm and immunity can offer novel explanations of different susceptibilities to infection and can lead to therapeutic avenues in circadian immune modulation of infectious diseases.

Drug reprofiling history and potential therapies against Parkinson's disease.

Given the high whittling down rates, high costs, and moderate pace of new medication, revelation, and improvement, repurposing "old" drugs to treat typical and uncommon illnesses is progressively becoming an appealing proposition. Drug repurposing is the way toward utilizing existing medications in treating diseases other than the purposes they were initially designed for. Faced with scientific and economic challenges, the prospect of discovering new medication indications is enticing to the pharmaceutical sector. Medication repurposing can be used at various stages of drug development, although it has shown to be most promising when the drug has previously been tested for safety. We describe strategies of drug repurposing for Parkinson's disease, which is a neurodegenerative condition that primarily affects dopaminergic neurons in the substantia nigra. We also discuss the obstacles faced by the repurposing community and suggest new approaches to solve these challenges so that medicine repurposing can reach its full potential.

Influence of the Gut Microbiota on the Development of Neurodegenerative Diseases.

Neurodegenerative disorders are marked by neuronal death over time, causing a variety of cognitive and motor dysfunctions. Protein misfolding, neuroinflammation, and mitochondrial and protein clearance system dysfunction have all been identified as common pathways leading to neurodegeneration in recent decades. An altered microbiome of the gut, which is considered to play a central role in diseases as well as health, has recently been identified as another potential feature seen in neurodegenerative disorders. An array of microbial molecules that are released in the digestive tract may mediate gut-brain connections and permeate many organ systems, including the nervous system. Furthermore, recent findings from clinical as well as preclinical trials suggest that the microbiota of the gut plays a critical part in gut-brain interplay and that a misbalance in the composition of the gut microbiome may be linked to the etiology of neurological disorders (majorly neurodegenerative health problems); the underlying mechanism of which is still unknown. The review aims to consider the association between the microbiota of the gut and neurodegenerative disorders, as well as to add to our understanding of the significance of the gut microbiome in neurodegeneration and the mechanisms that underlie it. Knowing the mechanisms behind the gut microbiome's role and abundance will provide us with new insights that could lead to novel therapeutic strategies.

Targeting Oxidative Stress Mechanisms to Treat Alzheimer's and Parkinson's Disease: A Critical Review.

Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) are becoming more frequent as the age increases. Contemporary therapies provide symptom resolution instead of targeting underlying pathological pathways. Consequently, there is considerable heterogeneity in response to treatment. Research has elucidated multiple potential of pathophysiological mechanisms contributing to neurodegenerative conditions, among which oxidative stress pathways appear to be suitable drug targets. The oxidative stress pathway has given rise to numerous novel pharmacological therapies that may provide a new avenue for neurodegenerative diseases. For example, SKQ (plastoquinone), MitoVitE, vitamin E, SOD mimic, MitoTEMPO (SOD mimetic), and bioactive molecules like curcumin and vitamin C have indeed been examined. To better understand how oxidative stress contributes to neurodegenerative diseases (such as Alzheimer's and Parkinson's), we analyzed the medicinal qualities of medicines that target markers in the cellular oxidative pathways. The specific pathway by which mitochondrial dysfunction causes neurodegeneration will require more investigation. An animal study should be carried out on medications that tackle cellular redox mechanisms but are not currently licensed for use in the management of neurodegenerative conditions.

Melatonergic Receptors (Mt1/Mt2) as a Potential Additional Target of Novel Drugs for Depression.

A complex pathogenesis involving several physiological systems is theorized to underline the development of depressive disorders. Depression is accompanied by circadian regulation disruption and interaction with the functioning of both central and peripheral oscillators. Many aspects of melatonin function unite these systems. The use of drugs for circadian rhythm disorders could inspire a potential treatment strategy for depression. Melatonin plays an essential role in the regulation of circadian rhythms. It exerts effect by activating two types of melatonin receptors, type 1A (MT1) and 1B (MT2). These are G-protein-coupled receptors, predominantly located in the central nervous system. MT1/MT2 agonists could be a useful treatment approach according to all three prevalent theories of the pathogenesis of depression involving either monoamines, synaptic remodeling, or immune/inflammatory events. MT1/MT2 receptors can be a potential target for novel antidepressants with impact on concentrations of neurotrophins or neurotransmitters, and reducing levels of pro-inflammatory cytokines. There is an interesting cross-talk mediated via the physical association of melatonin and serotonin receptors into functional heteromers. The antidepressive and neurogenetic effects of MT1/MT2 agonists can also be caused by the inhibition of the acid sphingomyelinase, leading to reduced ceramide, or increasing monoamine oxidase A levels in the hippocampus. Compounds targeting MT1 and MT2 receptors could have potential for new anti-depressants that may improve the quality of therapeutic interventions in treating depression and relieving symptoms. In particular, a combined effect on MT1 and/or MT2 receptors and neurotransmitter systems may be useful, since the normalization of the circadian rhythm through the melatonergic system will probably contribute to improved treatment. In this review, we discuss melatonergic receptors as a potential additional target for novel drugs for depression.

Cognitive and affective disturbances in patients with Parkinson's disease: Perspectives for classifying of motor/neuropsychiatric subtypes.

Parkinson's disease (PD) is a neurological disorder, related to rigidity, bradykinesia, and resting tremors, among other motor symptoms. It is noticed in the increasing frequency of neuropsychiatric disorders, which may be also caused by non-motor symptoms of PD. Treatment of PD is usually based on the classification of motor subtypes; however, it remains unclear whether motor subtypes have differences in the severity of psychiatric symptoms. It determines the importance of discovering possible neuropsychiatric subtypes of PD. We conducted a clinical study, which included group 1 - patients with postural instability and gait disorders dominant (PIGD) subtype, group 2 - patients with tremor dominant (TD) and indeterminate subtypes (non-PIGD), and group 3 - people who did not have CNS damage. We used the Montreal Cognitive Assessment, Russified 20-point version of the Toronto Alexithymia Scale, State-Trait Anxiety Inventory, and Beck Depression Inventory for assessment of the mental status. It was the first time that neuropsychiatric subtypes of PD had been investigated based on the condition of cognition and mood. Cluster analysis gave us the possibility to classify our patients by the following subtype: affective-cognitive PIGD, anxious PIGD, affective-cognitive non-PIGD, and non-PIGD without psychiatric symptoms. This indicates a closed link between psychiatric and motor symptoms, which can be used for the improved treatment of PD.

Circadian rhythm disorder and anxiety as mental health complications in post-COVID-19.

In 2020, the world gained dramatic experience of the development of the 2019 coronavirus disease pandemic (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Recent researches notice an increasing prevalence of anxiety and circadian rhythm disorders during COVID-19 pandemic. The aim of the study was describing clinical features of circadian rhythm disorders and the level of anxiety in persons who have had COVID-19. We have conducted a cohort retrospective study that included 278 patients who were divided into 2 study groups according to medical history: group 1 includes patients with a history of COVID-19; group 2 consists of patients who did not have clinically confirmed COVID-19 and are therefore considered not to have had this disease. To objectify circadian rhythm disorders, they were verified in accordance with the criteria of the International Classification of Sleep Disorders-3. The level of anxiety was assessed by the State-Trait Anxiety Inventory. The most common circadian rhythm disorders were sleep phase shifts. We found that COVID-19 in the anamnesis caused a greater predisposition of patients to the development of circadian rhythm disorders, in particular delayed sleep phase disorder. In addition, it was found that after COVID-19 patients have increased levels of both trait and state anxiety. In our study, it was the first time that relationships between post-COVID-19 anxiety and circadian rhythm disorders had been indicated. Circadian rhythm disorders are associated with increased trait and state anxiety, which may indicate additional ways to correct post-COVID mental disorders and their comorbidity with sleep disorders.

THE ROLE OF CIRCADIAN REGULATION OF GHRELIN LEVELS IN PARKINSON'S DISEASE (LITERATURE REVIEW).

The paper is aimed at the analysis of the role of the circadian regulation of ghrelin levels in patients with Parkinson's disease. Based on the literature data, patients with Parkinson's disease have clinical fluctuations in the symptoms of the disease, manifested by the diurnal changes in motor activity, autonomic functions, sleep-wake cycle, visual function, and the efficacy of dopaminergic therapy. Biological rhythms are controlled by central and peripheral oscillators which links with dopaminergic neurotransmission - core of the pathogenesis of Parkinson`s disease. Circadian system is altered in Parkinson`s disease due to that ghrelin fluctuations may be changed. Ghrelin is potential food-entrainable oscillator because it is linked with clock genes expression. In Parkinson`s disease this hormone may induce eating behavior changing and as a result metabolic disorder. The "hunger hormone" ghrelin can be a biomarker of the Parkinson's disease, and the study of its role in the pathogenesis, as well as its dependence on the period of the day, intake of levodopa medications to improve the effectiveness of treatment is promising.