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.

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 molecular approach of COX and LOX in Alzheimer's and Parkinson's disorder.

Neuroinflammation is well established biomarker for the major neurodegenerative like Alzheimer's disease (AD) and Parkinson's disease (PD). Cytokines/chemokines excite phospholipase A2 and cyclooxygenases (COX), facilitating the release of arachidonic acid (AA) and docosahexaenoic acid (DHA) from membrane glycerophospholipids, in which the former is oxidized to produce pro-inflammatory eicosanoids (prostaglandins, leukotrienes and thromboxane's), which intensify the neuroinflammatory events in the brain. Similarly, resolvins and neuroprotectins are the metabolized products of docosahexaenoic acid, which exert an inhibitory effect on the production of eicosanoids. Furthermore, an oxidized product of arachidonic acid, lipoxin, is generated via 5-lipoxygenase (5-LOX) pathway, and contributes to the resolution of inflammation, along with anti-inflammatory actions. Moreover, DHA and its lipid mediators inhibit neuroinflammatory responses by blocking NF-κB, inhibiting eicosanoid production, preventing cytokine secretion and regulating leukocyte trafficking. Various epidemiological studies reported, elevated levels of COX-2 enzyme in patients with AD and PD, indicating its role in progression of the disease. Similarly, enhanced levels of 5-LOX and 12/15-LOX in PD models represent their role brain disorders, where the former is expressed in AD patients and the latter exhibits it involvement in PD. The present review elaborates the role of AA, DHA, eicosanoids and docosanoids, along with COX and LOX pathway which provides an opportunity to the researchers to understand the role of these lipid mediators in neurological disorders (AD and PD). The information gathered from the review will aid in facilitating the development of appropriate therapeutic options targeting COX and LOX pathway.

The malleable brain: plasticity of neural circuits and behavior - a review from students to students.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815.

Beneficial effect of antidepressants against rotenone induced Parkinsonism like symptoms in rats.

Parkinson's disease is a second most common age-related neurodegenerative disorder characterized by the loss of DA neurons of SNpc region of the midbrain. Neurotransmitter dysfunction is involved in the pathogenesis of PD. Antidepressants like venlafaxine and sertraline expected to improve Parkinsonism like symptoms by modulating the levels of various neurotransmitters. The neuroprotective role of antidepressants is well explored in various CNS disorders. Therefore, this study was designed to explore and compare the mechanistic role of different antidepressants (venlafaxine and sertraline) against rotenone induced Parkinsonism like symptoms in rats. Rats were administrated with rotenone (1.5mg/kg/day; s.c.) daily for a period of 28 days. Venlafaxine (10 and 20mg/kg; p.o.), sertraline (10 and 20mg/kg; p.o.) and Levodopa combination with Carbidopa (10mg/kg; p.o.) were administered daily starting from 7th day one hour prior to rotenone administration. Behavioral parameters (body weight, rotarod, grip strength, narrow beam walk and open field) were assessed on weekly basis. On 28th day, animals were sacrificed and striatum were isolated for biochemical (LPO, GSH and nitrite), neuroinflammatory (TNF-α, IL-1ß and IL-6), neurochemical (DA, NE, 5-HT, GABA, Glutamate, DOPAC, HVA and 5-HIAA) and mitochondrial complex-I estimation. Rotenone administration significantly reduced body weight, motor coordination, oxidative defense, increased pro-inflammatory mediators and decreased level of catecholamines. Pre-treatment with venlafaxine and sertraline significantly attenuated the alteration in behavioral, oxidative stress, neuroinflammatory, mitochondrial and catecholamines level in striatum. The study provides a hope that these drugs could be used as adjuvant therapy in the management and treatment of PD.

Beneficial effect of zinc chloride and zinc ionophore pyrithione on attenuated cardioprotective potential of preconditioning phenomenon in STZ-induced diabetic rat heart.

Ischemic preconditioning (IPC) is well demonstrated to produce cardioprotection by phosphorylation and subsequent inactivation of glycogen synthase kinase-3ß (GSk-3ß) in the normal rat heart, but its effect is attenuated in the diabetic rat heart. This study was designed to investigate the effect of zinc chloride and zinc ionophore pyrithione (ZIP) on the attenuated cardioprotective potential of IPC in the diabetic rat heart. Diabetes mellitus (DM) was induced by a single intraperitoneal administration of streptozotocin (STZ) (50 mg/kg; i.p). The isolated perfused rat heart was subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. Myocardial infarct size was estimated by triphenyltetrazolium chloride (TTC) staining and cardiac injury was measured by estimating lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) in the coronary effluent. Also, GSK-3ß was measured and neutrophil accumulation was measured by estimating myeloperoxidase (MPO) levels. IPC significantly decreased the myocardial infarct size, the release of LDH and CK-MB, the GSK-3ß levels and the MPO levels in the normal rat heart. Pre- and post-ischemic treatment with zinc chloride and zinc ionophore pyrithione (ZIP) in the normal and diabetic rat hearts significantly decreased the myocardial infarct size, the level of CK-MB and LDH in the coronary effluent and GSK-3ß and MPO levels. Our results suggest that pharmacological preconditioning with zinc chloride and ZIP significantly restored the attenuated cardioprotective potential of IPC in the diabetic rat heart.

Piperine Enhances the Protective Effect of Curcumin Against 3-NP Induced Neurotoxicity: Possible Neurotransmitters Modulation Mechanism.

3-Nitropropionic acid (3-NP) is a fungal toxin well established model used for inducing symptoms of Huntington's disease. Curcumin a natural polyphenol has been reported to possess neuroprotective activity by decreasing oxidative stress. The aim of present study was to investigate neuroprotective effect of curcumin with piperine (bioavailability enhancer) against 3-NP induced neurotoxicity in rats. Administration of 3-NP (10 mg/kg for 21 days) showed loss in body weight, declined motor function and changes in biochemical (LPO, nitrite and glutathione level), neuroinflammatory (TNF-α and IL-1ß level) and neurochemical (DA, NE, 5-HT, DOPAC, 5-HIAA and HVA). Chronic treatment with curcumin (25 and 50 mg/kg) and curcumin (25 mg/kg) with piperine (2.5 mg/kg) once daily for 21 days prior to 3-NP administration. All the behavioral parameters were studied at 1st, 7th, 14th, and 21st day. On 22nd day all the animals was scarified and striatum was separated. Curcumin alone and combination (25 mg/kg) with piperine (2.5 mg/kg) showed beneficial effect against 3-NP induced motor deficit, biochemical and neurochemical abnormalities in rats. Piperine (2.5 mg/kg) with curcumin (25 mg/kg) significantly enhances its protective effect as compared with curcumin alone treated group. The results of the present study indicate that protective effect of curcumin potentiated in the presence of piperine (bioavailability enhancer) against 3-NP-induced behavioral and molecular alteration.

Polymeric microparticles-based formulation for the eradication of cutaneous candidiasis: development and characterization.

Cutaneous candidiasis is a common topical fungal infection which may be more prominent in patients associated with AIDS. It is usually treated by conventional formulations such as cream, gel, which show various adverse effects on skin along with systemic absorption. To overcome these drawbacks, various novel drug delivery systems have been explored. Poly(lactic-co-glycolic acid) (PLGA)-based microparticulate systems have shown good dermal penetration after topical application. Therefore, in the present study clotrimazole-loaded PLGA microspheres were prepared for targeted dermal delivery. Microspheres were prepared by using a single emulsification (oil-in-water, O/W) evaporation technique and characterized for different parameters. Prepared microparticulate systems were dispersed in Carbopol 934® gel and antifungal activity was carried out on experimentally induced cutaneous candidiasis in immunosuppressed guinea pigs. Particle size of optimized formulation was 2.9 µm along with 74.85% entrapment of drug. Skin retention studies revealed that drug accumulation in the skin was higher with microspheres gel as compared to marketed gel. Confocal microscopy of skin further confirmed penetration of microspheres up to 50 µm into the dermal region. In-vivo antifungal activity studies demonstrated that microsphere gel showed better therapeutic activity, lowest number of cfu/ml was recorded, as compared to marketed gel after 96 h of application. Based on the results of the study, it can be concluded that PLGA microparticles may be promising carriers to deliver clotrimazole intradermally for the treatment of invasive fungal infections.

A review on polyamines as promising next-generation neuroprotective and anti-aging therapy.

Neurodegenerative disorders are diseases characterized by progressive degeneration of neurons and associated structures and are a major global issue growing more widespread as the global population's average age increases. Despite several investigations on their etiology, the specific cause of these disorders remains unknown. However, there are few symptomatic therapies to treat these disorders. Polyamines (PAs) (putrescine, spermidine, and spermine) are being studied for their role in neuroprotection, aging and cognitive impairment. They are ubiquitous polycations which have relatively higher concentrations in the brain and possess pleiotropic biochemical activities, including regulation of gene expression, ion channels, mitochondria Ca2+ transport, autophagy induction, programmed cell death, and many more. Their cellular content is tightly regulated, and substantial evidence indicates that their altered levels and metabolism are strongly implicated in aging, stress, cognitive dysfunction, and neurodegenerative disorders. In addition, dietary polyamine supplementation has been reported to induce anti-aging effects, anti-oxidant effects, and improve locomotor abnormalities, and cognitive dysfunction. Thus, restoring the polyamine level is considered a promising pharmacological strategy to counteract neurodegeneration. This review highlights PAs' physiological role and the molecular mechanism underpinning their proposed neuroprotective effect in aging and neurodegenerative disorders.

Transient Impairment in Microglial Function Causes Sex-Specific Deficits in Synaptic and Hippocampal Function in Mice Exposed to Early Adversity.

Abnormal development and function of the hippocampus are two of the most consistent findings in humans and rodents exposed to early life adversity, with males often being more affected than females. Using the limited bedding (LB) paradigm as a rodent model of early life adversity, we found that male adolescent mice that had been exposed to LB exhibit significant deficits in contextual fear conditioning and synaptic connectivity in the hippocampus, which are not observed in females. This is linked to altered developmental refinement of connectivity, with LB severely impairing microglial-mediated synaptic pruning in the hippocampus of male and female pups on postnatal day 17 (P17), but not in adolescent P33 mice when levels of synaptic engulfment by microglia are substantially lower. Since the hippocampus undergoes intense synaptic pruning during the second and third weeks of life, we investigated whether microglia are required for the synaptic and behavioral aberrations observed in adolescent LB mice. Indeed, transient ablation of microglia from P13-21, in normally developing mice caused sex-specific behavioral and synaptic abnormalities similar to those observed in adolescent LB mice. Furthermore, chemogenetic activation of microglia during the same period reversed the microglial-mediated phagocytic deficits at P17 and restored normal contextual fear conditioning and synaptic connectivity in adolescent LB male mice. Our data support an additional contribution of astrocytes in the sex-specific effects of LB, with increased expression of the membrane receptor MEGF10 and enhanced synaptic engulfment in hippocampal astrocytes of 17-day-old LB females, but not in LB male littermates. This finding suggests a potential compensatory mechanism that may explain the relative resilience of LB females. Collectively, these studies highlight a novel role for glial cells in mediating sex-specific hippocampal deficits in a mouse model of early-life adversity.

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.

Age-associated sex difference in the expression of mitochondria-based redox sensitive proteins and effect of pioglitazone in nonhuman primate brain.

BACKGROUND: Paraoxonase 2 (PON2) and neuronal uncoupling proteins (UCP4 and UCP5) possess antioxidant, anti-apoptotic activities and minimize accumulation of reactive oxygen species in mitochondria. While age and sex are risk factors for several disorders that are linked with oxidative stress, no study has explored the age- and sex-dependent expression of PON2 isoforms, UCP4 and UCP5 in primate brain or identified a drug to activate UCP4 and UCP5 in vivo. Preclinical studies suggest that the peroxisome proliferator-activated receptor gamma agonist, pioglitazone (PIO), can be neuroprotective, although the mechanism responsible is unclear. Our previous studies demonstrated that pioglitazone activates PON2 in primate brain and we hypothesized that pioglitazone also induces UCP4/5. This study was designed to elucidate the age- and sex-dependent expression of PON2 isoforms, UCP4 and UCP5, in addition to examining the impact of systemic PIO treatment on UCP4 and UCP5 expression in primate brain. METHODS: Western blot technique was used to determine the age- and sex-dependent expression of UCP4 and UCP5 in substantia nigra and striatum of African green monkeys. In addition, we tested the impact of daily oral pioglitazone (5 mg/kg/day) or vehicle for 1 or 3 weeks on expression of UCP4 and UCP5 in substantia nigra and striatum in adult male monkeys. PIO levels in plasma and cerebrospinal fluid (CSF) were determined using LC-MS. RESULTS: We found no sex-based difference in the expression of PON2 isoforms, UCP4 and UCP5 in striatum and substantia nigra of young monkeys. However, we discovered that adult female monkeys exhibit greater expression of PON2 isoforms than males in substantia nigra and striatum. Our data also revealed that adult male monkeys exhibit greater expression of UCP4 and UCP5 than females in substantia nigra but not in striatum. PIO increased UCP4 and UCP5 expression in substantia nigra and striatum at 1 week, but after 3 weeks of treatment this activation had subsided. CONCLUSIONS: Our findings demonstrate a sex-, age- and region-dependent profile to the expression of PON2, UCP4 and UCP5. These data establish a biochemical link between PPARγ, PON2, UCP4 and UCP5 in primate brain and demonstrate that PON2, UCP4 and UCP5 can be pharmacologically stimulated in vivo, revealing a novel mechanism for observed pioglitazone-induced neuroprotection. We anticipate that these outcomes will contribute to the development of novel neuroprotective treatments for Parkinson's disease and other CNS disorders.

Parkinson's disease (PD) is less common in women than men, which may be related to the protective effect of high levels of estrogens in women that maintain the activity of neuroprotective proteins in brain mitochondria. Our previous work suggests that paraoxonase-2 (PON2), uncoupling protein-4 (UCP4) and uncoupling protein-5 (UCP5) play vital roles in maintaining the health of brain dopamine neurons that are lost in PD. This work tested the hypothesis that female primate brains expresses higher levels of these proteins than males. In addition, this research investigated whether estrogen regulates the expression these factors and whether they can be pharmacologically activated later in life to protect dopamine neurons at a time when symptoms of PD typically emerge. The results indicate that before puberty when estrogen levels in females are relatively low, there is no difference in PON2, UCP4, UCP5 brain levels between males and females, but in adults PON2 is up to 3 × higher in females compared with males in regions relevant to PD, consistent with estrogen activation of PON2. Earlier studies have shown that pioglitazone can be neuroprotective in several adverse brain conditions, although the mechanism is not clear. The current research demonstrates that pioglitazone transiently activates by about twofold the expression of PON2, UCP4, UCP5 in vivo in primate brain, suggesting their involvement in the neuroprotective properties of the drug. Overall, the current data provides impetus for further work on activating protective factors that alter mitochondrial dynamics and function, leading to improved understanding and treatment of multiple diseases.

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.

miRNA-encapsulated abiotic materials and biovectors for cutaneous and oral wound healing: Biogenesis, mechanisms, and delivery nanocarriers.

MicroRNAs (miRNAs) as therapeutic agents have attracted increasing interest in the past decade owing to their significant effectiveness in treating a wide array of ailments. These polymerases II-derived noncoding RNAs act through post-transcriptional controlling of different proteins and their allied pathways. Like other areas of medicine, researchers have utilized miRNAs for managing acute and chronic wounds. The increase in the number of patients suffering from either under-healing or over-healing wound demonstrates the limited efficacy of the current wound healing strategies and dictates the demands for simpler approaches with greater efficacy. Various miRNA can be designed to induce pathway beneficial for wound healing. However, the proper design of miRNA and its delivery system for wound healing applications are still challenging due to their limited stability and intracellular delivery. Therefore, new miRNAs are required to be identified and their delivery strategy needs to be optimized. In this review, we discuss the diverse roles of miRNAs in various stages of wound healing and provide an insight on the most recent findings in the nanotechnology and biomaterials field, which might offer opportunities for the development of new strategies for this chronic condition. We also highlight the advances in biomaterials and delivery systems, emphasizing their challenges and resolutions for miRNA-based wound healing. We further review various biovectors (e.g., adenovirus and lentivirus) and abiotic materials such as organic and inorganic nanomaterials, along with dendrimers and scaffolds, as the delivery systems for miRNA-based wound healing. Finally, challenges and opportunities for translation of miRNA-based strategies into clinical applications are discussed.

Expression of PON2 isoforms varies among brain regions in male and female African green monkeys.

Mitochondrial dysfunction and oxidative stress contribute to the neuropathology of neurodegenerative disorders such as Parkinson's disease (PD). Paraoxonase-2 (PON2) is a mitochondrial protein that mitigates oxidative stress, enhances mitochondrial function and exhibits anti-inflammatory properties. Previously, we have documented sex-based variation in PON2 with higher brain PON2 expression in female (2-fold) as compared to male African green monkeys. This aim of this study is to identify PON2 isoforms and explore the region-based variations in the protein level of PON2 in brain of African green monkeys. Male and female brain tissue samples (striatum, hippocampus, occipital cortex, dorsolateral prefrontal cortex) from African green monkeys (Chlorocebus sabaeus) were analyzed by western blotting technique for PON2 expression. We found two PON2 isoforms (39 and 41 kDa) in each examined brain region of male and female monkeys. Male monkeys showed no significant difference in the expression level of PON2 isoforms among different brain regions whereas female monkeys showed a significant difference in the expression level of PON2 isoforms in all examined regions except dorsolateral prefrontal cortex. In addition, the result revealed highest expression of PON2 protein in striatum compared to other brain regions in both male and female monkeys. This report is the first to quantify expression of PON2 isoforms in different brain regions and it also establishes the existence of sex as well as region-based variation in PON2 protein expression in primate brain. Since PON2 serves a protective role for dopaminergic neurons it should be considered as a druggable target for oxidative stress-related neurodegenerative disorders like PD. We anticipate that the outcome of this study will contribute to the development of neuroprotective strategies in PD.

Pioglitazone transiently stimulates paraoxonase-2 expression in male nonhuman primate brain: Implications for sex-specific therapeutics in neurodegenerative disorders.

Paraoxonase-2 (PON2) enhances mitochondria function and protects against oxidative stress. Stimulating its expression has therapeutic potential for diseases where oxidative stress plays a significant role in the pathology, such as Parkinson's disease. Clinical and preclinical evidence suggest that the anti-diabetic drug pioglitazone may provide neuroprotection in Parkinson's disease, Alzheimer's disease, and stroke, but the biochemical pathway(s) responsible has not been fully elucidated. To determine the effect of pioglitazone on PON2 expression we treated male African green monkeys with oral pioglitazone (5 mg/kg/day) for 1 and 3 weeks. We found that pioglitazone increased PON2 mRNA and protein expression in brain following 1 week of treatment, however, by 3 weeks of treatment PON2 expression had returned to baseline. This transient increase was detected in substantia nigra, striatum, hippocampus, and dorsolateral prefrontal cortex The short-term impact of pioglitazone on PON2 expression in striatum may contribute to the discrepancy in the potency of the drug between short-term animal models and clinical trials for Parkinson's disease. Both PON2 and pioglitazone's receptor, peroxisome proliferator-activated receptor gamma (PPARγ), possess sex- and brain region-dependent expression, which may play a role in the short-term effect of pioglitazone and provide clues to extending the beneficial effects of PON2 activation.

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.

Sex-based disparity in paraoxonase-2 expression in the brains of African green monkeys.

The development of several neurodegenerative disorders, such as Parkinson's disease, has been linked with decreased mitochondrial performance, leading to oxidative stress as a result of increased production of reactive oxygen species (ROS). Previous studies have established that the mitochondrial enzyme, paraoxonase-2 (PON2), possesses potent antioxidant and anti-inflammatory properties, with its expression linked with lower ROS levels. The aim of this study was to explore the sex-based variations in the protein level of PON2 in different brain regions (striatum, hippocampus, occipital cortex, and dorsolateral prefrontal cortex) of African green monkeys. Our results revealed that the PON2 expression in females was significantly higher than in males, in each of the examined brain regions. As Parkinson's disease is more prevalent in males compared with females and is characterized by oxidative stress in the nigrostriatal system, these findings add to the growing evidence for PON2 as a target for development of therapeutics to combat this disorder.

PPARγ/PGC1α signaling as a potential therapeutic target for mitochondrial biogenesis in neurodegenerative disorders.

Neurodegenerative diseases represent some of the most devastating neurological disorders, characterized by progressive loss of the structure and function of neurons. Current therapy for neurodegenerative disorders is limited to symptomatic treatment rather than disease modifying interventions, emphasizing the desperate need for improved approaches. Abundant evidence indicates that impaired mitochondrial function plays a crucial role in pathogenesis of many neurodegenerative diseases and so biochemical factors in mitochondria are considered promising targets for pharmacological-based therapies. Peroxisome proliferator-activated receptors-γ (PPARγ) are ligand-inducible transcription factors involved in regulating various genes including peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC1α). This review summarizes the evidence supporting the ability of PPARγ-PGC1α to coordinately up-regulate the expression of genes required for mitochondrial biogenesis in neurons and provide directions for future work to explore the potential benefit of targeting mitochondrial biogenesis in neurodegenerative disorders. We have highlighted key roles of NRF2, uncoupling protein-2 (UCP2), and paraoxonase-2 (PON2) signaling in mediating PGC1α-induced mitochondrial biogenesis. In addition, the status of PPARγ modulators being used in clinical trials for Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD) has been compiled. The overall purpose of this review is to update and critique our understanding of the role of PPARγ-PGC1α-NRF2 in the induction of mitochondrial biogenesis together with suggestions for strategies to target PPARγ-PGC1α-NRF2 signaling in order to combat mitochondrial dysfunction in neurodegenerative disorders.

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.