CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 22, Issue 10, 2023

The S100 protein is one of the calcium-binding proteins associated with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. S100 proteins are expressed in the central nervous system by oligodendrocytes, astrocytes and neurons during both normal and disease conditions. Although amyloid-beta aggregation and hyperphosphorylated tau plaques are the main pathological hallmarks of Alzheimer's disease, the S100 protein family is closely associated with neuroinflammation in several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis in addition to various types of cancer and other brain diseases. This review aims to present the key role of S100 proteins and their different relevant isoforms, along with the various approaches used for the regulation of these proteins in several neurodegenerative disorders.

Background: Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality today, which will surpass many infectious diseases in the coming years/decades. Posttraumatic epilepsy (PTE) is one of the most common debilitating consequences of TBI. PTE is a secondary, acquired epilepsy that causes recurrent, spontaneous seizures more than a week after TBI. The extent of head injury in individuals who develop PTE is unknown; however, trauma is thought to account for 20% of symptomatic epilepsy worldwide. Understanding the mechanisms of epilepsy following TBI is crucial for the discovery of new anticonvulsant drugs for the treatment of PTE, as well as for improving the quality of life of patients with PTE. Objective: This review article explains the rationale for the usage of a chemical model to access new treatments for post-traumatic epilepsy. Results: There are multiple methods to control and manage PTE. The essential and available remedy for the management of epilepsy is the use of antiepileptic drugs. Antiepileptic drugs (AEDs) decrease the frequency of seizures without affecting the disease's causality. Antiepileptic drugs are administrated for the prevention and treatment of PTE; however, 30% of epilepsy patients are drug-resistant, and AED side effects are significant in PTE patients. There are different types of animal models, such as the liquid percussion model, intracortical ferric chloride injection, and cortical subincision model, to study PTE and neurophysiological mechanisms underlying the development of epilepsy after head injury. However, these animal models do not easily mimic the pathological events occurring in epilepsy. Therefore, animal models of PTE are an inappropriate tool for screening new and putatively effective AEDs. Chemical kindling is the most common animal model used to study epilepsy. There is a strong similarity between the kindling model and different types of human epilepsy. Conclusion: Today, researchers use experimental animal models to evaluate new anticonvulsant drugs. The chemical kindling models, such as pentylenetetrazol, bicuculline, and picrotoxin-induced seizures, are important experimental models to analyze the impact of putative antiepileptic drugs.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting around 10 million people worldwide. Dopamine agonists that mimic the action of natural dopamine in the brain are the prominent drugs used in the management of PD symptoms. However, the therapy is limited to symptomatic relief with serious side effects. Phytocompounds have become the preferable targets of research in the quest for new pharmaceutical compounds. In addition, current research is directed towards determining a newer specific target for the better treatment and management of PD. Cav-1, a membrane protein present on the caveolae of the plasma membrane, acts as a transporter for lipid molecules in the cells. Cav-1 has been implicated in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease (AD), PD, etc. In this review, we have extensively discussed the role of Cav-1 protein in the pathogenesis of PD. In addition, molecular docking of some selective phytochemical compounds against Cav-1 protein (Q03135) was performed to understand their role. The best phytochemical compounds were screened based on their molecular interaction and binding affinity with the Cav-1 protein model.

Background: Multiple sclerosis (MS) is a lifelong deteriorating disease characterized by multiple heterogeneous symptoms. Being an autoimmune disease of the central nervous system, mainly affecting the myelin sheath of the nerves ordinarily results in neurological symptoms. GABA has numerous effects on the immune cells, altering cytokine production, cell migration and proliferation. Immune cells express GABA receptors making GABA an inflammation modulator. Therefore, GABAergic- associated agents could provide a compatible add-on therapy for MS patients alleviating their symptoms and providing better quality years. Objective: This review aims to highlight and provide evidence of the potential benefits of a secondary treatment option in MS patients, aiming to better manage this disease. Methods: We conducted a literature search through PubMed, Scopus and Google Scholar for GABA agonists, antagonists and modulators used in the in vivomodel of experimental autoimmune encephalomyelitis (EAE), taking into consideration certain inclusion and exclusion criteria. Results: In vivo studies for GABA-a and GABA-b agonists and modulators showed regulation of the autoimmune response in EAE mice. Increased preservation of myelinated sensitive fibers and diminished axonal damage in the CNS was also demonstrated. Further, decreased mononuclear inflammatory infiltration, pro-inflammatory cytokines reduction and reduced levels of Reactive oxygen species (ROS) were also reported. Biological results included decreased peak disease severity, duration, clinical scores and EAE incidence in the treatment groups. Conclusion: GABA agonists and modulators efficiently challenged different aspects of disease pathophysiology in vivo models of EAE. The studies showed a significant relevance of neuroprotection via modulation of the autoimmune response in EAE rats, indicating that they should be considered proper therapeutic candidates for clinical use, while also further clinical studies could empower their administration in clinical practice.

Parkinson's disease (PD) is a chronic and progressive neurological disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). The pathogenesis of PD is strongly related to mitochondrial dysfunction, oxidative stress, and neuroinflammation. This indicates that PD can be treated with anti-oxidative substitutes and anti-inflammatory compounds. The neuroprotective and anti-inflammatory effects of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists decrease cell death and halt the increase in neurodegeneration, which is why they have been given a lot of importance in research. Antidiabetic and anti-inflammatory effects have been observed to be generated by pioglitazone (PG), a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist that regulates neural plasticity in various neurodegenerative disorders. The neuroprotective and anti-inflammatory effects of PG are assessed in this article. It was found that the patients with DM who received PG treatment were noticeably at a lower risk of PD. However, some clinical studies have not proven a strong link between the therapeutic effects of PG on PD. As per suggestions of preclinical studies, the therapeutic effects of PG treatment include; increased life expectancy of neurons, decreased oxidative stress, halted microglial activity, lower inflammation (reduced NF-ΚB, COX-2, and iNOS), reduced mitochondrial dysfunction, rise in motor function (motor agility) and non-motor function (lowered cognitive dysfunction). In conclusion, we determined that PG exerts neuroprotective and anti-inflammatory effects in PD models and it can be considered a potential therapeutic candidate for PD.

Over the past 20 years, advances in the field of pathogenesis have inspired researchers to look into novel pharmacological therapeutics that are more focused on the pathophysiological events of the disease (AD). This review article discussed the prior use of statins for the prevention of Alzheimer's disease, which can help prevent the disease. Other drugs, such as memantine and donepezil, are available, but they cannot prevent the onset of AD in middle age. Based on available clinical data, the valuable effects of statins are mediated by alteration of β-amyloid (Aβ) and tau metabolism, genetic and lifestyle risk factors, along with other clinical aspects of AD. These findings suggested that using statins in middle age may help to prevent Alzheimer's disease by modifying genetic and non-genetic risk factors in later stages of life. In the present review, we elaborated upon the modification of risk factors and amyloid metabolism in the development and progression of AD and their modulation through atorvastatin. Future directions in the research and treatment of Alzheimer's disease patients include the use of antisense oligonucleotides (ASO) to change target expression, and researchers discovered decreased markers of oxidative stress in tissues affected by tau pathology in response to RNA interference treatment.

Background and Objective: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta, resulting in the loss of dopamine in the striatum, leading thus to the PD classic movement symptoms: resting tremor, rigidity, and bradykinesia/akinesia. Furthermore, Levodopa's efficacy declines with long-term use, generating serious motor complications. Neuroprotection implies the use of different agents exhibiting various neuroprotective strategies to prevent brain degeneration and neuron loss. The present review aims to summarize and analyze the natural neuroprotective compounds that have been tested against PD induced by the 6-hydroxydopamine (6-OHDA) in zebrafish. Results: The current study collected 23 different natural substances, divided into five distinct categories, namely herbal extracts, herbal formulations, bioactive compounds, marine products, and marine extracts. They modulate various signaling pathways involved in PD pathogenesis and exhibit specific activities such as an anxiolytic profile, improving locomotor impairment, restoring memory troubles, preventing DNA loss, inhibiting acetylcholinesterase, reducing lipid peroxidation and antiinflammatory activity, and enhancing the brain antioxidant enzymes. Conclusion and Perspectives: This review discusses the most promising natural neuroprotective compounds that have been evaluated for their potential efficiency on the 6-OHDA-induced lesions in the zebrafish model. These natural substances deserve further consideration for determination of their optimum concentrations, bioavailability, and their ability to cross the blood-brain-barrier to exert their effects on PD. Furthermore, a complete understanding of the molecular mechanisms involved in PD and larger epidemiologic and randomized clinical trials in humans is also required.

Considerable functional and structural alterations, or plasticity, in the central nervous system (CNS) are accompanied by numerous chronic pain syndromes. Sensitization of the peripheral (primary hyperalgesia) or central (secondary hyperalgesia) nervous system as unhelpful neuroplasticity may result in stimulus-induced pain (hyperalgesia and allodynia). Furthermore, nociception induces extensive plasticity in the peripheral and central neural systems in pathological disease states. Diseaseinduced plasticity at both structural and functional levels is evident as alterations in different molecules, synapses, cellular function and network activity. In the present article, we review plasticityinduced pain and pain-induced plasticity. Moreover, we will review the pain matrix. Furthermore, we will focus on recent developments of CNS alterations in long-lasting pain in some clinical entities encountered in rehabilitation. These clinical entities comprise nonspecific low back pain, complex regional pain syndrome, postamputation phantom pain, fibromyalgia, and chronic pain after spinal cord injury. Moreover, we will review the clinical treatment for the inhibition of pathological pain.

Background: A circadian pattern for the onset of acute ischemic stroke (AIS) has been described, with a higher risk in the early morning and a lower risk during nighttime. However, data assessing the circadian distribution of hemorrhagic transformation after intravenous thrombolysis (ivT) are still incongruent. Objectives: This review aimed to evaluate whether the time interval based on AIS onset or ivT time could influence the occurrence of intracranial hemorrhage (ICH) related to ivT and if the circadian rhythm of endogenous production of tissue plasminogen activator (t-PA) favors ICH occurrence. Methods: We conducted a systematic review following the PRISMA guidelines, searching PubMed and Embase for articles in English using the keywords: 'stroke', 'thrombolysis', and 'circadian'. Articles investigating the AIS onset or ivT time effects on circadian variations of ICH in AIS adult patients treated with ivT were included. Based on ICH's incidence and odds ratio, time intervals associated with higher risk and time intervals associated with lower risk were defined. The Newcastle-Ottawa Scale was used to assess the risk of bias. The resulting data were reported in a qualitative narrative synthesis. Results: From the 70 abstracts returned by electronic literature search, six studies with 33,365 patients fulfilled the inclusion criteria, out of which three were retrospective analysis studies, one case-control study, one prospective study, and one post hoc analysis of a multicentre trial. Some studies assessed the relationship between ICH occurrence and circadian rhythm depending on AIS onset time (n = 2), treatment time (n = 2), or both (n = 4). All studies investigated the patients' comorbidities as confounding variables for the circadian pattern of symptomatic ICH (sICH). Two studies found no association between AIS onset or ivT time and patient risk factors, but the other four found several differences and used multivariate logistic regression models to balance these covariates. The overall score of the Newcastle- Ottawa scale was 83.3%, which might be interpreted as overall high quality. Conclusion: ICH occurred after ivT seems to follow a circadian pattern; the 18:00-00:00 time frame was the safest one, and patients with AIS onset or ivT time between these hours had the lowest incidence of any ICH, including sICH. The 06:00-12:00 block was associated with the highest incidence of ICH and sICH. However, the analysis is limited by the small number of included studies and the heterogeneous findings reported. Further homogenized studies using comparable time frames and sICH definitions are needed to demonstrate this circadian pattern. The review protocol was registered in the OSF database under reference UHNF, doi:10.17605/OSF.IO/UHNF6.

Background: Alzheimer's disease (AD) is one of the most common irreversible degenerative diseases of the central nervous system. Recent studies have found that patients with AD generally experience abnormal glucose metabolism. Xylitol is a functional sugar alcohol, which has been reported to regulate glucose metabolism. Objective: The present study was designed to determine whether xylitol can alleviate cognitive impairment in AD mice. Methods: In the current research, 5% xylitol was supplemented in the diet to treat APP/PS1 transgenic AD mice for 2 months. Cognitive ability was measured by the Morris water maze, and anxiety-like behaviors were examined by open-field experiment. Hippocampal cellular apoptosis and mitochondria pathway related apoptotic proteins were tested by TUNEL staining and immunoblotting, respectively. By LC-MS, plasma levels of glucose metabolism intermediates and related amino acids were evaluated. Results: Results showed that xylitol could significantly ameliorate anxiety-like activity in AD mice by partially regulating expression levels of mitochondrial pathway-related apoptotic proteins. Xylitolregulated glucose metabolism may play an important role in the process. Conclusion: The current study suggests that xylitol may be a potential candidate for improving neuropsychiatric behavior in AD by regulating the levels of TCA cycle intermediates and related amino acids in glucose metabolism.

Background: Psychosocial stress (STS) is a common stress in modern societies. Chronic STS is associated with the impairment of a broad range of cognitive functions in humans and with prolonged abnormalities in memory. Matrix metalloproteinases (MMPs), a protein family of zinccontaining endopeptidases, are essential in neuro-inflammation and involved in neurodegenerative diseases. L-Car possessed neuroprotective, antioxidant, and anti-inflammatory properties and was shown to modulate MMPs. Objective: The current study aimed to examine the protective effect of L-Carnitine (L-CAR) on STSinduced changes in serum corticosterone levels, MMP-2, -9, and -12 protein and mRNA expression in the hippocampus as a possible mechanism for L-CAR protective effect on STS-induced memory impairment. Methods: The chronic STS and L-CAR (300 mg/kg/day, i.p) were simultaneously administered for 6 weeks to adult male Wistar rats. Serum corticosterone and protein levels of MMP-2, -9 and -12 were evaluated using ELISA. Real-Time PCR techniques were used to determine the mRNA levels of MMP-2, -9 and -12 in the hippocampus. Results: The findings showed that serum corticosterone levels and MMP-2 and -9 protein levels were significantly increased (p<0.05) in the STS group compared to the control. Similarly, RT-PCR findings showed that the mRNA of those proteinases significantly increased (p<0.05) following the intruder method. On the other hand, the administration of L-CAR restored the alterations in corticosterone levels and MMPs gene and protein expression induced by chronic STS. Conclusion: STS induced elevations in corticosterone and MMP-2 and -9 levels in the hippocampus. L-CAR, on the other hand, exhibited protective effects against the STS-induced changes in MMP-2 and -9.

Aim: The aim of the study is to check whether dyngo-4a can inhibit neuroblastoma (NB) proliferation and induce NB cell differentiation Background: Dynamin plays a role in regulating neurotransmission, signaling pathways, nutrient uptake, and pathogen infection, enhancing cell proliferation, tumor invasion, and metastasis. Studies have reported that dyngo-4a, a dynamin inhibitor, can be used to identify potential biomarkers and promising novel therapeutic targets for cancer treatment. Objective: To our knowledge, no published reports are showing that dynamin inhibitors can reduce NB cell proliferation and induce differentiation. In this study, we report that dyngo-4a can inhibit NB proliferation and induce NB cell differentiation. Methods: In this study, mouse neuroblastoma (Neuro-2a) cells were cultured in the presence or absence of dyngo-4a or retinoic acid (RA), or in the presence of both dyngo-4a and RA, or in the presence of sequential administration of dyngo-4a and RA to compare the effects on the inhibition of cell proliferation and effects on neuroblastoma cell differentiation induction. The neural cell markers, Nestin and Tuj 1 (Neuron-specific class III beta-tubulin), were used to demonstrate that the differentiated cells have neuronal cell features. The phosphorylation of Protein Kinase B (AKT), extracellular signalregulated kinases1/2 (ERK1/2), and epidermal growth factor receptor (EGFR) were determined to examine the potential mechanisms of induced differentiation. Results: Dyngo-4a or RA or dyngo-4a with subsequent RA administration induced Neuro-2a cell differentiation. However, RA with subsequent dyngo-4a administration results in almost total death of the Neuro-2a cells. The differentiation rate induced by dyngo-4a was significantly higher than the rate by RA treatment (72.5 ± 1.4% vs. 52.9 ± 3.1% with neuron features, P<0.05; 39.0 ± 0.8% vs. 29.9 ± 1.8% for axons under light microscopy, p<0.05). The differentiation rate of cells treated with dyngo-4a first, followed by RA, was greater than when they were added together (74.8 ± 3.8% vs. 10.6 ± 3.6%; 45.5 ± 1.6% vs. 12.4 ± 0.6%, p<0.01). Co-administration of dyngo-4a and RA at the same time diminished differentiation efficacy significantly. Dyngo-4a induced Neuro-2a cell differentiation and increased Tuj-1 positive staining by the 6^th day post- treatment. Dyngo-4a also inhibited Neuro-2a cell proliferation in a dose-dependent manner. Regarding the mechanism, dyngo-4a treatment showed a significant increase in p-AKT and p-ERK1/2 but not in p-EGFR. Conclusion: At a level comparable to RA, dynamin inhibition with dyngo-4a lowers proliferation and causes differentiation of Neuro-2a mouse NB cells in vitro. The AKT pathway is activated by dynago- 4a, which results in differentiation. The combination of RA with dynago-4a reduces the efficiency of differentiation. The application of dynago-4a followed by RA, on the other hand, enhances the differentiating effect, implying alternative mechanistic roles in the process.