Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model.

Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAAB]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient AspaNur7/Nur7 mice lowers [NAAB] and suppresses development of spongiform leukodystrophy.

Suppressing N-Acetyl-l-Aspartate Synthesis Prevents Loss of Neurons in a Murine Model of Canavan Leukodystrophy.

Canavan disease is a leukodystrophy caused by aspartoacylase (ASPA) deficiency. The lack of functional ASPA, an enzyme enriched in oligodendroglia that cleaves N-acetyl-l-aspartate (NAA) to acetate and l-aspartic acid, elevates brain NAA and causes "spongiform" vacuolation of superficial brain white matter and neighboring gray matter. In children with Canavan disease, neuroimaging shows early-onset dysmyelination and progressive brain atrophy. Neuron loss has been documented at autopsy in some cases. Prior studies have shown that mice homozygous for the Aspa nonsense mutation Nur7 also develop brain vacuolation. We now report that numbers of cerebral cortical and cerebellar neurons are decreased and that cerebral cortex progressively thins in AspaNur7/Nur7 mice. This neuronal pathology is prevented by constitutive disruption of Nat8l, which encodes the neuronal NAA-synthetic enzyme N-acetyltransferase-8-like. SIGNIFICANCE STATEMENT: This is the first demonstration of cortical and cerebellar neuron depletion and progressive cerebral cortical thinning in an animal model of Canavan disease. Genetic suppression of N-acetyl-l-aspartate (NAA) synthesis, previously shown to block brain vacuolation in aspartoacylase-deficient mice, also prevents neuron loss and cerebral cortical atrophy in these mice. These results suggest that lowering the concentration of NAA in the brains of children with Canavan disease would prevent or slow progression of neurological deficits.

Changes in Methionine Metabolism and Histone H3 Trimethylation Are Linked to Mitochondrial Defects in Multiple Sclerosis.

Mitochondrial changes, including decreased expression of electron transport chain subunit genes and impaired energetic, have been reported in multiple sclerosis (MS), but the mechanisms involved in these changes are not clear. To determine whether epigenetic mechanisms are involved, we measured the concentrations of methionine metabolites by liquid chromatography tandem mass spectrometry, histone H3 methylation patterns, and markers of mitochondrial respiration in gray matter from postmortem MS and control cortical samples. We found decreases in respiratory markers as well as decreased concentrations of the methionine metabolites S-adenosylmethionine, betaine, and cystathionine in MS gray matter. We also found expression of the enzyme betaine homocysteine methyltransferase in cortical neurons. This enzyme catalyzes the remethylation of homocysteine to methionine, with betaine as the methyl donor, and has previously been thought to be restricted to liver and kidney in the adult human. Decreases in the concentration of the methyl donor betaine were correlated with decreases in histone H3 trimethylation (H3K4me3) in NeuN+ neuronal nuclei in MS cortex compared with controls. Mechanistic studies demonstrated that H3K4me3 levels and mitochondrial respiration were reduced in SH-SY5Y cells after exposure to the nitric oxide donor sodium nitroprusside, and betaine was able to rescue H3K4me3 levels and respiratory capacity in these cells. Chromatin immunoprecipitation experiments showed that betaine regulates metabolic genes in human SH-SY5Y neuroblastoma cells. These data suggest that changes to methionine metabolism may be mechanistically linked to changes in neuronal energetics in MS cortex. SIGNIFICANCE STATEMENT: For decades, it has been observed that vitamin B12 deficiency and multiple sclerosis (MS) share certain pathological changes, including conduction disturbances. In the present study, we have found that vitamin B12-dependent methionine metabolism is dysregulated in the MS brain. We found that concentrations of the methyl donor betaine are decreased in MS cortex and are correlated with reduced levels of the histone H3 methyl mark H3K4me3 in neurons. Cell culture and chromatin immunoprecipitation-seq data suggest that these changes may lead to defects in mitochondria and impact neuronal energetics. These data have uncovered a novel pathway linking methionine metabolism with mitochondrial respiration and have important implications for understanding mechanisms involved in neurodegeneration in MS.

Silymarin- and melatonin-mediated changes in the expression of selected genes in pesticides-induced Parkinsonism.

Parkinson's disease (PD) is the second most unconcealed neurodegenerative disorder labelled with motor impairments. Two pesticides, manganese ethylene-1,2-bisdithiocarbamate (maneb) and 1,1'-dimethyl-4,4'-bipyridinium dichloride (paraquat), together, are reported to increase the incidence of PD in humans and Parkinsonism in mice. Conversely, silymarin and melatonin, two naturally occurring antioxidants, rescue from maneb- and paraquat-induced Parkinsonism. The study examined silymarin- and melatonin-mediated changes in the expression of selected genes in maneb- and paraquat-induced Parkinsonism employing mouse discover chips microarrays. The mice were treated intraperitoneally (i.p.), daily, with silymarin (40 mg/kg) or melatonin (30 mg/kg) for 9 weeks along with vehicles. Subsets of animals were also treated with maneb (30 mg/kg; i.p.) and paraquat (10 mg/kg; i.p.), twice a week, for 9 weeks. Whilst the expression of genes in the striatum was determined by microarray, the expression of randomly selected transcripts was validated by quantitative real-time polymerase chain reaction (qRT-PCR). Combined maneb- and paraquat-treatment altered the expression of several genes associated with apoptosis, inflammation, cell cycle, cell-signalling, etc. pathways. Silymarin and melatonin significantly resisted the changes in the expression of a few genes related to apoptosis, inflammation, cell cycle, cell-signalling, etc. The expression patterns of seven randomly selected genes were analyzed by qRT-PCR, which were found to follow the similar trends, as observed with microarray. The results obtained from the study thus demonstrate that despite resemblances, silymarin and melatonin differentially offset maneb- and paraquat-induced changes in transcriptome.

Chemical recycling of waste clothes: a smarter approach to sustainable development.

Amount of fabric waste has increased many folds in the past few years due to increasing population and rapidly changing fashiosn trends. Its larger portion being dumped in the landfills is creating a lot of problem in its management. This is causing problems to environmental components of earth, viz., air, water, and land. Chemically, cotton-based fabrics are made up of mainly cellulose with small components of other chemicals and contribute to a big segment of overall textiles. Along with donating the cloths for various purposes, scientific solutions are also feasible for valorizing waste fabrics to value-added products. This review article focuses on important strategies for addressing fabric waste for their possible conversion to significant products of varied applications. It emphasizes on chemical routes suitable for this purpose for producing cellulose, sugar, composites, etc. This will provide an insight to the readers for understanding the chemical significance of waste fabric and exploring the best possible ways for its efficient management, ensuring a step ahead towards sustainable development.

NAT8L mRNA oxidation is linked to neurodegeneration in multiple sclerosis.

RNA oxidation has been implicated in neurodegeneration, but the underlying mechanism for such effects is unclear. Extensive RNA oxidation occurs within the neurons in multiple sclerosis (MS) brains. Here, we identified selectively oxidized mRNAs in neuronal cells that pertained to neuropathological pathways. N-acetyl aspartate transferase 8 like (NAT8L) is one such transcript, whose translation product enzymatically synthesizes N-acetyl aspartic acid (NAA), a neuronal metabolite important for myelin synthesis. We reasoned that impediment of translation of an oxidized NAT8L mRNA will result in a reduction in its cognate protein, thus lowering the NAA level. This hypothesis is supported by our studies on cells, an animal model, and postmortem human MS brain. Reduced brain NAA level hampers myelin integrity making neuronal axons more susceptible to damage, which contributes to MS neurodegeneration. Overall, this work provides a framework for a mechanistic understanding of the link between RNA oxidation and neurodegeneration.

Melatonin or silymarin reduces maneb- and paraquat-induced Parkinson's disease phenotype in the mouse.

Oxidative stress is reported as one of the most widely accepted mechanisms of maneb (MB)- and paraquat (PQ)-induced nigrostriatal dopaminergic neurodegeneration leading to the Parkinson's disease (PD) phenotype. The study investigated the effects of silymarin, an antioxidant of plant origin, and melatonin, an indoleamine produced in all species, in MB- and PQ-induced mouse model of PD. The mice were treated intraperitoneally daily with silymarin (40mg/kg) or melatonin (30mg/kg) along with respective controls for 9wk. Subsets of these animals were also treated with MB (30mg/kg) and PQ (10mg/kg), twice a week, for 9wk, 2hr after silymarin/melatonin treatment. Locomotor activities along with striatal dopamine content, tyrosine hydroxylase (TH) immunoreactivity, number of degenerating neurons, lipid peroxidation and nitrite content were estimated. Additionally, mRNA expression of vesicular monoamine transporter, cytochrome P-450 2E1 (CYP2E1), and glutathione-S-transferase A4-4 (GSTA4-4), catalytic activities of CYP2E1 and GSTA4-4 and protein expressions of unphosphorylated and phosphorylated p53 (p53 and P-p53), Bax and caspase 9 were measured in control and MB- and PQ-treated mice with either silymarin or melatonin treatments. Silymarin/melatonin significantly offset MB- and PQ-mediated reductions in locomotor activities, dopamine content, TH immunoreactivity, VMAT 2 mRNA expression and the expression of p53 protein. Silymarin/melatonin attenuated the increases in lipid peroxidation, number of degenerating neurons, nitrite content, mRNA expressions of cytochrome P-450 2E1 (CYP2E1) and GSTA4-4, catalytic activities of CYP2E1 and GST and P-p53, Bax and caspase 9 protein expressions. The results demonstrate that silymarin and melatonin offer nigrostriatal dopaminergic neuroprotection against MB- and PQ-induced PD by the modulation of oxidative stress and apoptotic machinery.

The BHMT-betaine methylation pathway epigenetically modulates oligodendrocyte maturation.

Research into the epigenome is of growing importance as a loss of epigenetic control has been implicated in the development of neurodegenerative diseases. Previous studies have implicated aberrant DNA and histone methylation in multiple sclerosis (MS) disease pathogenesis. We have previously reported that the methyl donor betaine is depleted in MS and is linked to changes in histone H3 trimethylation (H3K4me3) in neurons. We have also shown that betaine increases histone methyltransferase activity by activating chromatin bound betaine homocysteine S-methyltransferase (BHMT). Here, we investigated the role of the BHMT-betaine methylation pathway in oligodendrocytes. Immunocytochemistry in the human MO3.13 cell line, primary rat oligodendrocytes, and tissue from MS postmortem brain confirmed the presence of the BHMT enzyme in the nucleus in oligodendrocytes. BHMT expression is increased 2-fold following oxidative insult, and qRT-PCR demonstrated that betaine can promote an increase in expression of oligodendrocyte maturation genes SOX10 and NKX-2.2 under oxidative conditions. Chromatin fractionation provided evidence of a direct interaction of BHMT on chromatin and co-IP analysis indicates an interaction between BHMT and DNMT3a. Our data show that both histone and DNA methyltransferase activity are increased following betaine administration. Betaine effects were shown to be dependent on BHMT expression following siRNA knockdown of BHMT. This is the first report of BHMT expression in oligodendrocytes and suggests that betaine acts through BHMT to modulate histone and DNA methyltransferase activity on chromatin. These data suggest that methyl donor availability can impact epigenetic changes and maturation in oligodendrocytes.

Omics in mechanistic and predictive toxicology.

High-throughput omics strategies delineate the molecular mechanism of toxicity, predict the toxicity of newer drugs and chemicals, and identify individuals at high risks on the basis of expression patterns of messenger ribonucleic acids, genes, and proteins, and detection of intermediary metabolites. Despite being a developing country, India is one of the fastest growing nations in the usages and applications of omics technologies. Several differentially expressed genes and proteins under various pathological and toxicant-exposed conditions have been identified, and many association studies on genetic polymorphisms with toxicant-induced diseases have been conducted for the predictive and mechanistic purposes. To date, omics-driven approaches have identified some novel fingerprints associated with disease risk/protection and prediction of toxicity of newer chemicals. Although the contributions of such findings in the mechanistic toxicology have been immense, predictive values of these findings in toxicology have been limited. In this review, the current status of omics-based research and its future possibilities at the Indian Institute of Toxicology Research (IITR), Lucknow, India, have been discussed.

Increased blood-brain barrier hyperpermeability coincides with mast cell activation early under cuprizone administration.

The cuprizone induced animal model of demyelination is characterized by demyelination in many regions of the brain with high levels of demyelination in the corpus callosum as well as changes in neuronal function by 4-6 weeks of exposure. The model is used as a tool to study demyelination and subsequent degeneration as well as therapeutic interventions on these effects. Historically, the cuprizone model has been shown to contain no alterations to blood-brain barrier integrity, a key feature in many diseases that affect the central nervous system. Cuprizone is generally administered for 4-6 weeks to obtain maximal demyelination and degeneration. However, emerging evidence has shown that the effects of cuprizone on the brain may occur earlier than measurable gross demyelination. This study sought to investigate changes to blood-brain barrier permeability early in cuprizone administration. Results showed an increase in blood-brain barrier permeability and changes in tight junction protein expression as early as 3 days after beginning cuprizone treatment. These changes preceded glial morphological activation and demyelination known to occur during cuprizone administration. Increases in mast cell presence and activity were measured alongside the increased permeability implicating mast cells as a potential source for the blood-brain barrier disruption. These results provide further evidence of blood-brain barrier alterations in the cuprizone model and a target of therapeutic intervention in the prevention of cuprizone-induced pathology. Understanding how mast cells become activated under cuprizone and if they contribute to blood-brain barrier alterations may give further insight into how and when the blood-brain barrier is affected in CNS diseases. In summary, cuprizone administration causes an increase in blood-brain barrier permeability and this permeability coincides with mast cell activation.

Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.

Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Ibrutinib Resistance Mechanisms and Treatment Strategies for B-Cell lymphomas.

Chronic activation of B-cell receptor (BCR) signaling via Bruton tyrosine kinase (BTK) is largely considered to be one of the primary mechanisms driving disease progression in B-Cell lymphomas. Although the BTK-targeting agent ibrutinib has shown promising clinical responses, the presence of primary or acquired resistance is common and often leads to dismal clinical outcomes. Resistance to ibrutinib therapy can be mediated through genetic mutations, up-regulation of alternative survival pathways, or other unknown factors that are not targeted by ibrutinib therapy. Understanding the key determinants, including tumor heterogeneity and rewiring of the molecular networks during disease progression and therapy, will assist exploration of alternative therapeutic strategies. Towards the goal of overcoming ibrutinib resistance, multiple alternative therapeutic agents, including second- and third-generation BTK inhibitors and immunomodulatory drugs, have been discovered and tested in both pre-clinical and clinical settings. Although these agents have shown high response rates alone or in combination with ibrutinib in ibrutinib-treated relapsed/refractory(R/R) lymphoma patients, overall clinical outcomes have not been satisfactory due to drug-associated toxicities and incomplete remission. In this review, we discuss the mechanisms of ibrutinib resistance development in B-cell lymphoma including complexities associated with genomic alterations, non-genetic acquired resistance, cancer stem cells, and the tumor microenvironment. Furthermore, we focus our discussion on more comprehensive views of recent developments in therapeutic strategies to overcome ibrutinib resistance, including novel BTK inhibitors, clinical therapeutic agents, proteolysis-targeting chimeras and immunotherapy regimens.

Vitamin K enhances the production of brain sulfatides during remyelination.

Multiple sclerosis (MS) is a devastating neurological disease, which is characterized by multifocal demyelinating lesions in the central nervous system. The most abundant myelin lipids are galactosylceramides and their sulfated form, sulfatides, which together account for about 27% of the total dry weight of myelin. In this study we investigated the role of vitamin K in remyelination, by using an animal model for MS, the cuprizone model. Demyelination was induced in C57Bl6/J mice, by feeding them a special diet containing 0.3% cuprizone (w/w) for 6 weeks. After 6 weeks, cuprizone was removed from the diet and mice were allowed to remyelinate for either 1 or 3 weeks, in the absence or presence of vitamin K (i.p. phylloquinone, 2mg, three times per week). Vitamin K enhanced the production of total brain sulfatides, after both 1 week and 3 weeks of remyelination (n = 5, P-values were <0.0001), when compared with the control group. To determine whether or not there is a synergistic effect between vitamins K and D for the production of brain sulfatides, we employed a similar experiment as above. Vitamin K also increased the production of individual brain sulfatides, including d18:1/18:0, d18:1/20:0, d18:1/24:0, and d18:1/24:1 after 3 weeks of remyelination, when compared to the control group. In addition, vitamin D enhanced the production of total brain sulfatides, as well as d18:1/18:0, d18:1/24:0, and d18:1/24:1 sulfatides after 3 weeks of remyelination, but no synergistic effect between vitamins K and D for the production of total brain sulfatides was observed.

Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology.

Multiple sclerosis (MS) is characterized by demyelination and progressive neurological disability. Previous studies have reported defects to mitochondria in MS including decreased expression of nuclear encoded electron transport chain subunit genes and inhibition of respiratory complexes. We previously reported increased levels of the hemoglobin ß subunit (Hbb) in mitochondrial fractions isolated from postmortem MS cortex compared to controls. In the present study, we performed immunohistochemistry to determine the distribution of Hbb in postmortem MS cortex and identified proteins which interact with Hbb by liquid chromatography tandem mass spectrometry (LC-MS/MS). We found that Hbb was enriched in pyramidal neurons in internal layers of the cortex and interacts with subunits of ATP synthase, histones, and a histone lysine demethylase. We also found that Hbb is present in the nucleus and that expression of Hbb in SH-SY5Y neuroblastoma cells increased trimethylation of histone H3 on lysine 4 (H3K4me3), a histone mark that regulates cellular metabolism. These data suggest that Hbb may be a part of a mechanism linking neuronal energetics with epigenetic changes to histones in the nucleus and may provide neuroprotection in MS by supporting neuronal metabolism.

Mechanism of Nanotization-Mediated Improvement in the Efficacy of Caffeine Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism.

The study aimed to measure the neuroprotective efficacy of caffeine-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles over bulk and to delineate the mechanism of improvement in efficacy both in vitro and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinsonism. Caffeine-encapsulated PLGA nanoparticles exhibited more pronounced increase in the endurance of dopaminergic neurons, fibre outgrowth and expression of tyrosine hydroxylase (TH) and growth-associated protein-43 (GAP-43) against 1-methyl-4-phenylpyridinium (MPP+)-induced alterations in vitro. Caffeine-encapsulated PLGA nanoparticles also inhibited MPP(+)-mediated nuclear translocation of nuclear factor-kappa B (NF-κB) and augmented protein kinase B phosphorylation more potentially than bulk counterpart. Conversely, MPTP reduced the striatal dopamine and its metabolites and nigral TH immunoreactivity whereas augmented the nigral microglial activation and nigrostriatal lipid peroxidation and nitrite content, which were shifted towards normalcy by caffeine. The modulations were more evident in caffeine-encapsulated PLGA nanoparticles treated animals as compared with bulk. Moreover, the striatal caffeine and its metabolites were found to be significantly higher in caffeine-encapsulated PLGA nanoparticles-treated mice as compared with bulk. The results thus suggest that nanotization improves the protective efficacy of caffeine against MPTP-induced Parkinsonism owing to enhanced bioavailability, inhibition of the nuclear translocation of NF-κB and activation of protein kinase B phosphorylation.

Does restraining nitric oxide biosynthesis rescue from toxins-induced parkinsonism and sporadic Parkinson's disease?

Nitric oxide (NO) is an important inorganic molecule of the biological system owing to diverse physiological implications. NO is synthesised from a semi-essential amino acid L-arginine. NO biosynthesis is catalysed by a family of enzymes referred to as nitric oxide synthases (NOSs). NO is accused in many acute and chronic illnesses, which include central nervous system disorders, inflammatory diseases, reproductive impairments, cancer and cardiovascular anomalies. Owing to very unstable nature, NO gets converted into nitrite, peroxynitrite and other reactive nitrogen species that could lead to nitrosative stress in the nigrostriatal system. Nitrosative stress is widely implicated in Parkinson's disease (PD), and its beneficial and harmful effects are demonstrated in in vitro, rodent and primate models of toxins-induced parkinsonism and in the blood, cerebrospinal fluid and nigrostriatal tissues of sporadic PD patients. The current article updates the roles of NO and NOSs in sporadic PD and toxins-induced parkinsonism in rodents along with the scrutiny of how inhibitors of NOSs could open a new line of approach to moderately rescue from PD pathogenesis based on the existing literature. The article also provides a perspective concerning the lack of ample admiration to such an approach and how to minimise the underlying lacunae.

Nicotine-encapsulated poly(lactic-co-glycolic) acid nanoparticles improve neuroprotective efficacy against MPTP-induced parkinsonism.

For some instances of Parkinson disease (PD), current evidence in the literature is consistent with reactive oxygen species being involved in the etiology of the disease. The management of PD is still challenging owing to its ambiguous etiology and lack of permanent cure. Because nicotine offers neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, the neuroprotective efficacy of nicotine-encapsulated poly(lactic-co-glycolic) acid (PLGA) nanoparticles and the underlying mechanism of improved efficacy, if any, over bulk nicotine were assessed in this study. The selected indicators of oxidative stress, dopaminergic neurodegeneration and apoptosis, were measured in both in vitro and rodent models of parkinsonism in the presence or absence of "nanotized" or bulk nicotine. The levels of dopamine and its metabolites were measured in the striatum, nicotine and its metabolite in the nigrostriatal tissues while the immunoreactivities of tyrosine hydroxylase (TH), metallothionein-III (MT-III), inducible nitric oxide synthase (iNOS) and microglial activation were checked in the substantia nigra of controls and treated mice. GSTA4-4, heme oxygenase (HO)-1, tumor suppressor protein 53 (p53), caspase-3, lipid peroxidation (LPO), and nitrite levels were measured in the nigrostriatal tissues. Nicotine-encapsulated PLGA nanoparticles improved the endurance of TH-immunoreactive neurons and the number of fiber outgrowths and increased the mRNA expression of TH, neuronal cell adhesion molecule, and growth-associated protein-43 over bulk against 1-methyl-4-phenyl pyridinium ion-induced degeneration in the in vitro model. MPTP reduced TH immunoreactivity and levels of dopamine and its metabolites and increased microglial activation, expression of GSTA4-4, iNOS, MT-III, HO-1, p53, and caspase-3, and levels of nitrite and LPO. Whereas both bulk nicotine and nicotine-encapsulated PLGA nanoparticles modulated the changes toward controls, the modulation was more pronounced in nicotine-encapsulated PLGA nanoparticle-treated parkinsonian mice. The levels of nicotine and cotinine were elevated in nicotine-encapsulated PLGA nanoparticle-treated PD mouse brain compared with bulk. The results obtained from this study demonstrate that nanotization of nicotine improves neuroprotective efficacy by enhancing its bioavailability and subsequent modulation in the indicators of oxidative stress and apoptosis.

Melatonin as a neuroprotective agent in the rodent models of Parkinson's disease: is it all set to irrefutable clinical translation?

Parkinson's disease (PD), a neurodegenerative disorder, is characterized by the selective degeneration of the nigrostriatal dopaminergic neurons, continuing or permanent deficiency of dopamine, accretion of an abnormal form of alpha synuclein in the adjacent neurons, and dysregulation of ubiquitin proteasomal system, mitochondrial metabolism, permeability and integrity, and cellular apoptosis resulting in rigidity, bradykinesia, resting tremor, and postural instability. Melatonin, an indoleamine produced almost in all the organisms, has anti-inflammatory, anti-apoptotic, and anti-oxidant nature. Experimental studies employing 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), methamphetamine, rotenone, and maneb and paraquat models have shown an enormous potential of melatonin in amelioration of the symptomatic features of PD. Although a few reviews published previously have described the multifaceted efficacy of melatonin against MPTP and 6-OHDA rodent models, due to development and validation of the newer models as well as the extensive studies on the usage of melatonin in entrenched PD models, it is worthwhile to bring up to date note on the usage of melatonin as a neuroprotective agent in PD. This article presents an update on the usage and applications of melatonin in PD models along with incongruous observations. The impending implications in the clinics, success, limitations, and future prospective have also been discussed in this article.