In Vitro and In Vivo Investigations of Chromone Derivatives as Potential Multitarget-Directed Ligands: Cognitive Amelioration Utilizing a Scopolamine-Induced Zebrafish Model.

Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid ß aggregation. Three potent compounds, i.e., VN-3, VN-14, and VN-19 were identified that displayed remarkable activities against different targets. These compounds displayed IC50 values of 80 nM, 2.52 µM, and 140 nM against the AChE enzyme, respectively, and IC50 values of 2.07 µM, 70 nM, and 450 nM against the MAO-B isoform, respectively. VN-3 displayed potent activity against self-induced Aß1-42 aggregation with inhibition of 58.3%. In the ROS inhibition studies, the most potent compounds reduced the intracellular ROS levels up to 80% in SH-SY5Y cells at 25 µM concentration. The compounds were found to be neuroprotective and noncytotoxic even at a concentration of 25 µM against SH-SY5Y cells. In silico studies showed that the compounds were nicely accommodated in the active sites of the receptors along with thermodynamically stable orientations. Compound VN-19 exhibited a balanced multitargeting profile against AChE, BuChE, MAO-B, and Aß1-42 enzymes and was further evaluated for in vivo activities on the scopolamine-induced zebrafish model. VN-19 was found to ameliorate the cognitive decline in zebrafish brains by protecting them against scopolamine-induced neurodegeneration. Thus, VN-3, VN-14, and VN-19 were identified as potent multitarget-directed ligands with a balanced activity profile against different targets and can be developed as therapeutics for AD.

Calcium channelopathies in neurodegenerative disorder: an untold story of RyR and SERCA.

INTRODUCTION: Recent neuroscience breakthroughs have shed light on the sophisticated relationship between calcium channelopathies and movement disorders, exposing a previously undiscovered tale focusing on the Ryanodine Receptor (RyR) and the Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA). Calcium signaling mainly orchestrates neural communication, which regulates synaptic transmission and total network activity. It has been determined that RyR play a significant role in managing neuronal functions, most notably in releasing intracellular calcium from the endoplasmic reticulum. AREAS COVERED: It highlights the involvement of calcium channels such as RyR and SERCA in physiological and pathophysiological conditions. EXPERT OPINION: Links between RyR and SERCA activity dysregulation, aberrant calcium levels, motor and cognitive dysfunction have brought attention to the importance of RyR and SERCA modulation in neurodegenerative disorders. Understanding the obscure function of these proteins will open up new therapeutic possibilities to address the underlying causes of neurodegenerative diseases. The unreported RyR and SERCA narrative broadens the understanding of calcium channelopathies in movement disorders and calls for more research into cutting-edge therapeutic approaches.

Bacillus Calmette-Guérin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats.

Tardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 × 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.

Impact of noscapine on halting the progression of pentylenetetrazole induced kindling epilepsy in mice.

Epilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce 100% outcomes because of the complexity of the disease, poor diagnosis, and upsurge to drug-resistant epilepsy. The study repurposed the drug 'noscapine' mainly known for its anti-tussive properties. For the management of epilepsy and its associated secondary complications. To confirm the effect of noscapine, adult mice were injected with pentylenetetrazole (PTZ) (35 mg/kg i.p.) on an alternate day for 29 days to induce epilepsy. Animals were pretreated with noscapine in three doses (5, 10, and 20 mg/kg i.p.) for 33 days. Various behavioural assessments like the open field test, Morris water maze, and tail suspension test were performed to observe animals' locomotor activity, spatial memory, and anxiety-depressive behaviour. On the 34th day, animals were sacrificed, and brains were removed for biochemical estimations. Prolonged PTZ treatment reduced locomotor, learning activity, and increased anxiety-depressive behaviour, which was further confirmed by reduced antioxidant levels such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase because of increased oxido-nitrosative stress, that is, malondialdehyde (MDA) and nitrite in the brain. In comparison, noscapine pretreatment attenuated PTZ-induced behavioural and biochemical changes in the animals. The results indicate that noscapine ameliorates the oxido-nitrosative stress. However, studies indicate that oxido-nitrosative stress is a significant concern for the GABAergic neurons and promotes the disease progression. Further studies are required to explore the molecular mechanism of noscapine, which might be a practical approach as a newer antiepileptic agent.

Animal models of Huntington's disease and their applicability to novel drug discovery and development.

INTRODUCTION: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the CAG trinucleotide repeat in huntingtin (Htt) gene. The discovery of the HD-causing gene prompted the creation of new HD animal models, proving that mutations in the HD gene are linked to either loss of function of the wild-type (un-mutated) gene or toxic gain in the function of a mutated gene. AREAS COVERED: Animal models of HD have led to an increased understanding of its pathogenesis and resulted in the discovery of new therapeutic targets/drugs. The focus of this review is on the selection and validation of animal models for HD drug discovery. Furthermore, several drugs tested using various models in the preclinical phase have been compiled to demonstrate the applicability of these HD animal models. EXPERT OPINION: The applicability of animal models for HD drug discovery has been well demonstrated. Nevertheless, despite the enormous progression made to date, the development of drug therapy to completely alleviate disease progression has not been achieved. Most of the pre-clinically tested drugs have shown promising results in alleviating HD-associated neurodegeneration and motor and non-motor symptoms, but only a few of them thrived to produce satisfactory results in the clinical phase. This failure has raised concerns about the selection of HD animal models and species, and new strategies for selection are mandated.

An Overview of the Pathophysiological Mechanisms of 3-Nitropropionic Acid (3-NPA) as a Neurotoxin in a Huntington's Disease Model and Its Relevance to Drug Discovery and Development.

Animal models are used to better understand the various mechanisms involved in the pathogenesis of diseases and explore potential pathways that will aid in discovering therapeutic targets. 3-Nitropropionic Acid (3-NPA) is a neurotoxin used to induce Huntington's disease (HD)-like symptoms in experimental animals. The 3-NPA is a fungus toxin that impairs the complex II (succinate dehydrogenase) activity of the mitochondria and reduces ATP synthesis, leading to excessive production of free radicals resulting in the degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. This is characterized by motor impairments a key clinical manifestation of HD. 3-NPA has the potential to alter several cellular processes, including mitochondrial functions, oxidative stress, apoptosis, and neuroinflammation mimicking HD-like pathogenic conditions in animals. This review strives to provide a new insight towards the 3-NPA induced molecular dysfunctioning in developing an animal model of HD. Moreover, we summarise several preclinical studies that support the use of the 3-NPA-induced models for drug discovery and development in HD. This review is a collection of various articles that were published from 1977 to 2022 on Pubmed (1639), Web of Science (2139), and Scopus (2681), which are related to the 3-NPA induced animal model.

Involvement of the G-Protein-Coupled Estrogen Receptor-1 (GPER) Signaling Pathway in Neurodegenerative Disorders: A Review.

The G-protein-coupled estrogen receptor-1 (GPER) is an extranuclear estrogen receptor that regulates the expression of several downstream signaling pathways with a variety of biological actions including cell migration, proliferation, and apoptosis in different parts of the brain area. It is endogenously activated by estrogen, a steroidal hormone that binds to GPER receptors which help in maintaining cellular homeostasis and neuronal integrity as well as influences neurogenesis. In contrast, neurodegenerative disorders are a big problem for society, and still many people suffer from motor and cognitive impairments. Research to date reported that GPER has the potential to whittle down motor abnormalities and cognitive dysfunction by limiting the progression of neurodegenerative disorders. Although several findings suggest that GPER activation accelerated transcription of the PI3K/Akt/Gsk-3ß and ERK1/2 signaling pathway that halt disease progression by decreasing oxidative stress, neuroinflammation, and apoptosis. Accordingly, the goal of this review is to highlight the basic mechanism of GPER signaling pathway-mediated neuroprotection in various neurodegenerative disorders including Parkinson's disease (PD), Huntington's disease (HD), Tardive dyskinesia (TD), and Epilepsy. This review also discusses the role of the GPER activators which might be a promising therapeutic target option to treat neurodegenerative disorders. All the data were obtained from published articles in PubMed (353), Web of Science (788), and Scopus (770) databases using the search terms: GPER, PD, HD, TD, epilepsy, and neurodegenerative disorders.

Monkeypox infection: The past, present, and future.

Monkeypox is a zoonotic illness caused by the monkeypox virus (MPXV) that has a similar etiology to smallpox. The first case of monkeypox was reported in Western and Central Africa in 1971, and in 2003, there was an outbreak of monkeypox viruses outside Africa. According to the World Health Organization (WHO) and Center for Disease Control and Prevention (CDC), monkeypox is transmitted through direct contact with infected animals or persons exposed to infectious sores, scabs, or body fluids. Also, intimate contact between people during sex, kissing, cuddling, or touching parts of the body can result in the spreading of this disease. The use of the smallpox vaccine against monkeypox has several challenges and hence anti-virals such as cidofovir, brincidofovir, and tecovirimat have been used for the symptomatic relief of patients and reversing the lesion formation on the skin. Despite the recent outbreak of monkeypox most especially in hitherto non-endemic countries, there is still a lack of definitive treatment for monkeypox. In the present review, emphasis was focused on etiopathology, transmission, currently available therapeutic agents, and future targets that could be explored to halt the progression of monkeypox. From our review we can postulate that owing to the lack of a definitive cure to this reemerging disorder, there is a need for general awareness about the transmission as well as to develop appropriate diagnostic procedures, immunizations, and antiviral medication.

Nrf2/HO-1 Signaling Stimulation through Acetyl-11-Keto-Beta-Boswellic Acid (AKBA) Provides Neuroprotection in Ethidium Bromide-Induced Experimental Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a severe immune-mediated neurological disease characterized by neuroinflammation, demyelination, and axonal degeneration in the central nervous system (CNS). This is frequently linked to motor abnormalities and cognitive impairments. The pathophysiological hallmarks of MS include inflammatory demyelination, axonal injury, white matter degeneration, and the development of CNS lesions that result in severe neuronal degeneration. Several studies suggested downregulation of nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling is a causative factor for MS pathogenesis. Acetyl-11-keto-ß-boswellic acid (AKBA) is an active pentacyclictriterpenoid obtained from Boswellia serrata, possessing antioxidant and anti-inflammatory properties. The present study explores the protective potential of AKBA on behavioral, molecular, neurochemical, and gross pathological abnormalitiesandhistopathological alterations by H&E and LFB staining techniques in an experimental model of multiple sclerosis, emphasizing the increase inNrf2/HO-1 levels in the brain. Moreover, we also examine the effect of AKBA on the intensity of myelin basic protein (MBP) in CSF and rat brain homogenate. Specific apoptotic markers (Bcl-2, Bax, andcaspase-3) were also estimated in rat brain homogenate. Neuro behavioralabnormalities in rats were examined using an actophotometer, rotarod test, beam crossing task (BCT),and Morris water maze (MWM). AKBA 50 mg/kg and 100 mg/kg were given orally from day 8 to 35 to alleviate MS symptoms in the EB-injected rats. Furthermore, cellular, molecular, neurotransmitter, neuroinflammatory cytokine, and oxidative stress markers in rat whole brain homogenate, blood plasma, and cerebral spinal fluid were investigated. This study shows that AKBA upregulates the level of antioxidant proteins such as Nrf2 and HO-1 in the rat brain. AKBA restores altered neurochemical levels, potentially preventing gross pathological abnormalities during MS progression.

Neuroprotective efficacy of 4-Hydroxyisoleucine in experimentally induced intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a severe form of brain injury, which is a major cause of mortality in humans. Hydrocephalus and cerebral hematoma lead to severe neurological deficits. A single autologous blood (ALB) injection in rats' brains induces hemorrhage and other conditions that regularly interfere with the standard treatment of several cellular and molecular pathways. Several studies have found that IGF-1/GLP-1 decreases the production of inflammatory markers in peripheral tissues, while some have found that they also have pro-inflammatory functions. Since these receptors are down-regulated in hemorrhagic situations, we looked into the potential neuroprotective effect of 4-hydroxyisoleucine (4-HI); 50 mg/kg and 100 mg/kg, an active compound Trigonellafoenum-graecum, on post-hemorrhagic deficits in rats. Long-term oral administration of 4-HI for 35 days has improved behavioral and neurochemical deficits and severe pathological changes and improved cellular and molecular markers, apoptotic markers in the ALB-induced ICH experimental model. Furthermore, the findings revealed that 4-HI also improved the levels of other neurotransmitters (Ach, DOPA, GABA, glutamate); inflammatory cytokines (TNF-alpha, IL-1ß, IL-17), and oxidative stress markers (MDA, nitrite, LDH, AchE, SOD, CAT, GPx, GSH) in the brain when evaluated after Day 35. There is no proven treatment available for the prevention of post-brain hemorrhage and neurochemical malfunction; available therapy is only for symptomatic relief of the patient. Thus, 4-HI could be a potential clinical approach for treating post-brain haemorrhage and neurochemical changes caused by neurological damage. Furthermore, 4-HI may be linked to other standard therapeutic therapies utilized in ICH as a potential pharmacological intervention.

Inhibition of extracellular regulated kinase (ERK)-1/2 signaling pathway in the prevention of ALS: Target inhibitors and influences on neurological dysfunctions.

Cell signal transduction pathways are essential modulators of several physiological and pathological processes in the brain. During overactivation, these signaling processes may lead to disease progression. Abnormal protein kinase activation is associated with several biological dysfunctions that facilitate neurodegeneration under different biological conditions. As a result, these signaling pathways are essential in understanding brain disorders' development or progression. Recent research findings indicate the crucial role of extracellular signal-regulated kinase-1/2 (ERK-1/2) signaling during the neuronal development process. ERK-1/2 is a key component of its mitogen-activated protein kinase (MAPK) group, controlling certain neurological activities by regulating metabolic pathways, cell proliferation, differentiation, and apoptosis. ERK-1/2 also influences neuronal elastic properties, nerve growth, and neurological and cognitive processing during brain injuries. The primary goal of this review is to elucidate the activation of ERK1/2 signaling, which is involved in the development of several ALS-related neuropathological dysfunctions. ALS is a rare neurological disorder category that mainly affects the nerve cells responsible for regulating voluntary muscle activity. ALS is progressive, which means that the symptoms are getting worse over time, and there is no cure for ALS and no effective treatment to avoid or reverse. Genetic abnormalities, oligodendrocyte degradation, glial overactivation, and immune deregulation are associated with ALS progression. Furthermore, the current review also identifies ERK-1/2 signaling inhibitors that can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of ALS. As a result, in the future, the potential ERK-1/2 signaling inhibitors could be used in the treatment of ALS and related neurocomplications.

Understanding Abnormal c-JNK/p38MAPK Signaling Overactivation Involved in the Progression of Multiple Sclerosis: Possible Therapeutic Targets and Impact on Neurodegenerative Diseases.

Demyelination, immune dysregulation, and neuroinflammation are the most common triggers of motor neuron disorders such as multiple sclerosis (MS). MS is a chronic demyelinating neurodegenerative disease of the central nervous system caused by abnormal immune activation, which causes myelin sheath damage. Cell signal transduction pathways are required for a variety of physiological and pathological processes in the brain. When these signaling systems become overactive, they can lead to disease progression. In various physiological conditions, abnormal mitogen-activated protein kinase (MAPK) activation is associated with several physiological dysfunctions that cause neurodegeneration. Previous research indicates that c-JNK and p38MAPK signaling play critical roles in neuronal growth and differentiation. c-JNK/p38MAPK is a member of the MAPK family, which regulates metabolic pathways, cell proliferation, differentiation, and apoptosis that control certain neurological activities. During brain injuries, c-JNK/p38MAPK also affects neuronal elastic properties, nerve growth, and cognitive processing. This review systematically linked abnormal c-JNK/p38MAPK signaling activation to multiple neuropathological pathways in MS and related neurological dysfunctions. MS progression is linked to genetic defects, oligodendrocyte destruction, glial overactivation, and immune dysregulation. We concluded that inhibiting both the c-JNK/p38MAPK signaling pathways can promote neuroprotection and neurotrophic effects against the clinical-pathological presentation of MS and influence other neurological disorders. As a result, the potential benefits of c-JNK/p38MAPK downregulation for the development of disease-modifying treatment interventions in the future could include MS prevention and related neurocomplications.

Nrf2/HO-1 Signaling Activator Acetyl-11-keto-beta Boswellic Acid (AKBA)-Mediated Neuroprotection in Methyl Mercury-Induced Experimental Model of ALS.

Methylmercury (MeHg) is a potent neurotoxin that causes neurotoxicity and neuronal cell death. MeHg exposure also leads to oligodendrocyte destruction, glial cell overactivation, and demyelination of motor neurons in the motor cortex and spinal cord. As a result, MeHg plays an important role in the progression of amyotrophic lateral sclerosis (ALS)-like neurocomplications. ALS is a fatal neurodegenerative disorder in which neuroinflammation is the leading cause of further CNS demyelination. Nuclear factor erythroid-2-related factor-2 (Nrf2)/Heme oxygenase-1 (HO-1) signaling pathway was thought to be a potential target for neuroprotection in ALS. Acetyl-11-keto-beta-boswellic acid (AKBA) is a multi-component pentacyclic triterpenoid mixture derived from Boswellia serrata with anti-inflammatory and antioxidant properties. The research aimed to investigate whether AKBA, as a Nrf2 / HO-1 activator, can provide protection against ALS. Thus, we explored the role of AKBA on the Nrf2/HO-1 signaling pathway in a MeHg-induced experimental ALS model. In this study, ALS was induced in Wistar rats by oral gavage of MeHg 5 mg/kg for 21 days. An open field test, force swim test, and grip strength were performed to observe experimental rats' motor coordination behaviors. In contrast, a morris water maze was performed for learning and memory. Administration of AKBA 50 mg/kg and AKBA 100 mg/kg continued from day 22 to 42. Neurochemical parameters were evaluated in the rat's brain homogenate. In the meantime, post-treatment with AKBA significantly improved behavioral, neurochemical, and gross pathological characteristics in the brain of rats by increasing the amount of Nrf2/HO-1 in brain tissue. Collectively, our findings indicated that AKBA could potentially avoid demyelination and encourage remyelination.