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.

Berberine Ameliorate Haloperidol and 3-Nitropropionic Acid-Induced Neurotoxicity in Rats.

Berberine due to its antioxidant properties, has been used around the globe significantly to treat several brain disorders. Also, oxidative stress is a pathological hallmark in neurodegenerative diseases like Huntington's disease (HD) and Tardive dyskinesia (TD). Berberine an alkaloid from plants has been reported to have neuroprotective potential in several animal models of neurodegenerative diseases. Hence, this study aims to evaluate the neuroprotective effect of berberine in the animal model of 3-nitropropionic acid (3-NP) induced HD and haloperidol induced tardive dyskinesia with special emphasis on its antioxidant property. The study protocol was divided into 2 phases, first phase involved the administration of 3-NP and berberine at the dose of (25, 50, and 100 mg/kg) intraperitoneally (i.p) and orally (p.o.) respectively for 21 days, and the following parameters (rotarod, narrow beam walk and photoactometer) as a measure of motor activity and striatal and cortical levels of (LPO, GSH, SOD, catalase, and nitrate) evaluated as a measure of oxidative stress were assessed for HD. Similarly in the second phase, TD was induced by using haloperidol, for 21 days and berberine at the dose of (25, 50, and 100 mg/kg) was administered, and both physical and biochemical parameters were assessed as mentioned for the HD study. The resultant data indicated that berberine attenuate 3-NP and haloperidol-induced behavioral changes and improved the antioxidant capcity in rodents. Hence berberine might be a novel therapeutic candidate to manage TD & HD.

Role of vitamins and minerals as immunity boosters in COVID-19.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) known as coronavirus disease (COVID-19), emerged in Wuhan, China, in December 2019. On March 11, 2020, it was declared a global pandemic. As the world grapples with COVID-19 and the paucity of clinically meaningful therapies, attention has been shifted to modalities that may aid in immune system strengthening. Taking into consideration that the COVID-19 infection strongly affects the immune system via multiple inflammatory responses, pharmaceutical companies are working to develop targeted drugs and vaccines against SARS-CoV-2 COVID-19. A balanced nutritional diet may play an essential role in maintaining general wellbeing by controlling chronic infectious diseases. A balanced diet including vitamin A, B, C, D, E, and K, and some micronutrients such as zinc, sodium, potassium, calcium, chloride, and phosphorus may be beneficial in various infectious diseases. This study aimed to discuss and present recent data regarding the role of vitamins and minerals in the treatment of COVID-19. A deficiency of these vitamins and minerals in the plasma concentration may lead to a reduction in the good performance of the immune system, which is one of the constituents that lead to a poor immune state. This is a narrative review concerning the features of the COVID-19 and data related to the usage of vitamins and minerals as preventive measures to decrease the morbidity and mortality rate in patients with COVID-19.

Exploring the intricacies of calcium dysregulation in ischemic stroke: Insights into neuronal cell death and therapeutic strategies.

Calcium ion (Ca2+) dysregulation is one of the main causes of neuronal cell death and brain damage after cerebral ischemia. During ischemic stroke, the ability of neurons to maintain Ca2+ homeostasis is compromised. Ca2+ regulates various functions of the nervous system, including neuronal activity and adenosine triphosphate (ATP) production. Disruptions in Ca2+ homeostasis can trigger a cascade of events, including activation of the unfolded protein response (UPR) pathway, which is associated with endoplasmic reticulum (ER) stress and mitochondrial dysfunction. This response occurs when the cell is unable to manage protein folding within the ER due to various stressors, such as a high influx of Ca2+. Consequently, the UPR is initiated to restore ER function and alleviate stress, but prolonged activation can lead to mitochondrial dysfunction and, ultimately, cell death. Hence, precise regulation of Ca2+ within the cell is mandatory. The ER and mitochondria are two such organelles that maintain intracellular Ca2+ homeostasis through various calcium-operating channels, including ryanodine receptors (RyRs), inositol trisphosphate receptors (IP3Rs), sarco/endoplasmic reticulum calcium ATPases (SERCAs), the mitochondrial Na+/Ca2+ exchanger (NCLX), the mitochondrial calcium uniporter (MCU) and voltage-dependent anion channels (VDACs). These channels utilize Ca2+ sequestering and release mechanisms to maintain intracellular Ca2+ homeostasis and ensure proper cellular function and survival. The present review critically evaluates the significance of Ca2+ and its physiological role in cerebral ischemia. We have compiled recent findings on calcium's role and emerging treatment strategies, particularly targeting mitochondria and the endoplasmic reticulum, to address Ca2+ overload in cerebral ischemia.

Filgrastim, a Recombinant Form of Granulocyte Colony-stimulating Factor, Ameliorates 3-nitropropionic Acid and Haloperidol-induced Striatal Neurotoxicity in Rats.

Striatal neurotoxicity is the pathological hallmark for a heterogeneous group of movement disorders like Tardive dyskinesia (TD) and Huntington's disease (HD). Both diseases are characterized by progressive impairment in motor function. TD and HD share common features at both cellular and subcellular levels. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor (GCSF), shows neuroprotective properties in in-vivo models of movement disorders. This study seeks to evaluate the neuroprotective effect of filgrastim in haloperidol and 3-NP-induced neurotoxicity in rats. The study was divided into two: in study one, rats were administered with haloperidol for 21 days, filgrastim at the dose of (20, 40, 60 µg/kg,s.c.) was administered once a day before haloperidol treatment and the following parameters (orofacial movements, rotarod, actophotometer) were performed to assess TD. Similarly, in the second study, rats were administered with 3-NP for 21 days, filgrastim at a dose of (20 and 40 µg/kg, s.c.) was administered, and the following parameters (rotarod, narrow beam walk, and open field test) were assessed for HD. On the 22nd day, animals were sacrificed and cortex and striatum isolated for oxidative stress (LPO, GSH, SOD, catalase, and nitrate) marker assessment. Results revealed that haloperidol and 3-NP treatment significantly impaired motor coordination, and oxidative defense inducing TD and HD-like symptoms. Treatment with filgrastim significantly averted haloperidol and 3-NP-induced behavioral and biochemical alterations. Conclusively, the neuroprotective effect of filgrastim is credited to its antioxidant properties. Hence, filgrastim might be a novel therapeutic candidate for the management of TD and HD.

Neuroprotective effect of silymarin against 3-Nitropropionic acid-induced neurotoxicity in rats.

(HD) Huntington's disease is a severe hereditary catastrophic neurological disease with an autosomal dominant heritable changes manifested by cognitive, behavioural, and motor progression deficits, resulting in death. Several mechanisms are involved in the pathogenesis of this complex and rare disease, including excitotoxicity, mitochondrial dysfunction, neurotransmitters imbalance, and oxidative stress. Silymarin was selected as an investigational drug, due to its numerous activities in current research, it possesses substantial antioxidant and neuroprotective functionalities. The present research attempts, i.p. injections of 3-NPA (10 â€‹mg/kg) were given for 21 days to trigger Huntington-like symptoms in rats. The percentage fluctuations in body weight, the footfall counts, and the time required to transverse the beam and motor functions were analyzed at multiple time points. Oxidative stress markers like MDA/LPO, GSH, protein, nitrite, catalase, and superoxide dismutase levels were examined in the striatum region. The current study results conclusively demonstrate that chronic 3-NPA administration significantly decreased the body weight and showed marked abnormalities in motor coordination, locomotion, and increased striatal generation of free radicals. Furthermore, treatment with silymarin (100 & 200 â€‹mg/kg/p.o.), mitigated 3-NPA triggered behavioural and biochemical alterations. Our study results could conclude that Silymarin may be advantageous and might develop an adjuvant treatment for the management of Huntington's disease.

Animal models of attention-deficit hyperactivity disorder (ADHD).

Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous neuropsychiatric disorder characterized by three primary symptoms hyperactivity, attention deficit, and impulsiveness, observed in both children and adults. In childhood, this disorder is more common in boys than in girls, and at least 75% will continue to suffer from the disorder until adulthood. Individuals with ADHD generally have poor academic, occupational, and social functioning resulting from developmentally inappropriate levels of hyperactivity and impulsivity, as well as impaired ability to maintain attention on motivationally relevant tasks. Very few drugs available in clinical practice altogether abolish the symptoms of ADHD, therefore, to find new drugs and target it is essential to understand the neuropathological, neurochemical, and genetic alterations that lead to the progression of ADHD. With this contrast, an animal study is the best approach because animal models provide relatively fast invasive manipulation, rigorous hypothesis testing, as well as it provides a better angle to understand the pathological mechanisms involved in disease progression. Moreover, animal models, especially for ADHD, serve with good predictive validity would allow the assessment and development of new therapeutic interventions, with this aim, the present review collect the various animal models on a single platform so that the research can select an appropriate model to pursue his study.

Neuroprotection through G-CSF: recent advances and future viewpoints.

Granulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of hematopoietic growth factors, is 19.6 kDa glycoprotein which is responsible for the proliferation, maturation, differentiation, and survival of neutrophilic granulocyte lineage. Apart from its proven clinical application to treat chemotherapy-associated neutropenia, recent pre-clinical studies have highlighted the neuroprotective roles of G-CSF i.e., mobilization of haemopoietic stem cells, anti-apoptotic, neuronal differentiation, angiogenesis and anti-inflammatory in animal models of neurological disorders. G-CSF is expressed by numerous cell types including neuronal, immune and endothelial cells. G-CSF is released in autocrine manner and binds to its receptor G-CSF-R which further activates numerous signaling transduction pathways including PI3K/AKT, JAK/STAT and MAP kinase, and thereby promote neuronal survival, proliferation, differentiation, mobilization of hematopoietic stem and progenitor cells. The expression of G-CSF receptors (G-CSF-R) in the different brain regions and their upregulation in response to neuronal insult indicates the autocrine protective signaling mechanism of G-CSF by inhibition of apoptosis, inflammation, and stimulation of neurogenesis. These observed neuroprotective effects of G-CSF makes it an attractive target to mitigate neurodegeneration associated with neurological disorders. The objective of the review is to highlight and summarize recent updates on G-CSF as a therapeutically versatile neuroprotective agent along with mechanisms of action as well as possible clinical applications in neurodegenerative disorders including AD, PD and HD.

Gene therapy and immunotherapy as promising strategies to combat Huntington's disease-associated neurodegeneration: emphasis on recent updates and future perspectives.

INTRODUCTION: Modulation of gene expression using gene therapy as well as modulation of immune activation using immunotherapy has attracted considerable attention as rapidly emerging potential therapeutic intervention for the treatment of HD. Several preclinical and clinical trials for gene-based therapy and immunotherapy/antibody-based have been conducted. AREAS COVERED: This review focused on the potential use of gene therapy and immuno-based therapies to treat HD, including the current status, the rationale for these approaches as well as preclinical and clinical data supporting it. Growing knowledge of HD pathogenesis has resulted in the discovery of new therapeutic targets, some of which are now in clinical trials. Focus has been allocated to RNA and DNA-based gene therapies for the reduction of mutant huntingtin (mHTT), using Immuno/antibody-based therapies. EXPERT OPINION: While safety and efficacy of gene therapy and immunotherapy has been well demonstrated for HD, therefore much focus has now been shifted to disease-modifying therapies. This review defines the current status and future directions of gene therapy and immunotherapies. The review summarizes by what means HD genetic root cause modification and functional restoration of mHtt protein could be achieved by using targeted multimodality gene therapy and immunotherapy to target intracellular and extracellular mHtt.

Protective Effect of Hemin Against Experimental Chronic Fatigue Syndrome in Mice: Possible Role of Neurotransmitters.

Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and relapsing fatigue along with long-lasting and debilitating fatigue, myalgia, cognitive impairment, and many other common symptoms. The present study was conducted to explore the protective effect of hemin on CFS in experimental mice. Male albino mice were subjected to stress-induced CFS in a forced swimming test apparatus for 21 days. After animals had been subjected to the forced swimming test, hemin (5 and 10 mg/kg; i.p.) and hemin (10 mg/kg) + tin(IV) protoporphyrin (SnPP), a hemeoxygenase-1 (HO-1) enzyme inhibitor, were administered daily for 21 days. Various behavioral tests (immobility period, locomotor activity, grip strength, and anxiety) and estimations of biochemical parameters (lipid peroxidation, nitrite, and GSH), mitochondrial complex dysfunctions (complexes I and II), and neurotransmitters (dopamine, serotonin, and norepinephrine and their metabolites) were subsequently assessed. Animals exposed to 10 min of forced swimming session for 21 days showed a fatigue-like behavior (as increase in immobility period, decreased grip strength, and anxiety) and biochemical alteration observed by increased oxidative stress, mitochondrial dysfunction, and neurotransmitter level alteration. Treatment with hemin (5 and 10 mg/kg) for 21 days significantly improved the decreased immobility period, increased locomotor activity, and improved anxiety-like behavior, oxidative defense, mitochondrial complex dysfunction, and neurotransmitter level in the brain. Further, these observations were reversed by SnPP, suggesting that the antifatigue effect of hemin is HO-1 dependent. The present study highlights the protective role of hemin against experimental CFS-induced behavioral, biochemical, and neurotransmitter alterations.