HAT and HDAC: Enzyme with Contradictory Action in Neurodegenerative Diseases.

In view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors.

Neuroprotective Effects of Tinospora cordifolia via Reducing the Oxidative Stress and Mitochondrial Dysfunction against Rotenone-Induced PD Mice.

Oxidative stress and mitochondrial dysfunction are leading mechanisms that play a crucial role in the progression of Parkinson's disease (PD). Tinospora cordifolia shows a wide range of biological activities including immunomodulatory, antimicrobial, antioxidant, and anti-inflammatory properties. This study explored the neuroprotective activities of T. cordifolia ethanolic extract (TCE) against Rotenone (ROT)-intoxicated Parkinsonian mice. Four experimental groups of mice were formed: control, ROT (2 mg/kg body wt, subcutaneously), TCE (200 mg/kg body wt, oral) + ROT, and TCE only. Mice were pretreated with TCE for a week and then simultaneously injected with ROT for 35 days. Following ROT-intoxication, motor activities, antioxidative potential, and mitochondrial dysfunction were analyzed. Decrease in the activity of the mitochondrial electron transport chain (mETC) complex, loss of mitochondrial membrane potential (Ψm), increase in Bax/Bcl-2 (B-cell lymphoma 2) ratio, and caspase-3 expression are observed in the ROT-intoxicated mice group. Our results further showed ROT-induced reactive oxygen species (ROS)-mediated alpha-synuclein (α-syn) accumulation and mitochondrial dysfunction. However, pre- and cotreatment with TCE along with ROT-intoxication significantly reduced α-syn aggregation and improved mitochondrial functioning in cells by altering mitochondrial potential and increasing mETC activity. TCE also decreases the Bax/Bcl-2 ratio and also the expression of caspase-3, thus reducing apoptosis of the cell. Altogether, TCE is effective in protecting neurons from rotenone-induced cytotoxicity in the Parkinsonian mouse model by modulating oxidative stress, ultimately reducing mitochondrial dysfunction and cell death.

Curcumin Modulates p62-Keap1-Nrf2-Mediated Autophagy in Rotenone-Induced Parkinson's Disease Mouse Models.

Autophagy mediates self-digestion of abnormally aggregated proteins and organelles present in the cytoplasm. This mechanism may prove to be neuroprotective against Parkinson's disease (PD) by clearing misfolded α-synuclein (α-syn) aggregates from dopaminergic neurons. p62, an adaptor protein acts as a selective substrate for autophagy and regulates the formation as well as the degradation of protein aggregates. p62 sequesters keap1 freeing Nrf2 and consequently activating the transcription of its target genes. In the present study, we aimed to investigate the anti-parkinsonian activity of curcumin targeting primarily activation of autophagy via the Nrf2-Keap1 pathway. The mice were subcutaneously injected with rotenone (2.5 mg/kg bodyweight) and co-treated with oral administration of curcumin (80 mg/kg bodyweight) for 35 days. Following completion of dosing, motor activities, anti-oxidative potential, mitochondrial dysfunction, and various protein expressions, including Nrf2, Keap1, p62, LC3, Bcl2, Bax, and caspase 3, were assessed. The results revealed that curcumin restored the motor coordination and anti-oxidative activity while improving the mitochondrial functioning in PD mice. Autophagy was evaluated by the change in the expression of autophagic markers, p62 and LC3-II. Reduced p62 and LC3-II expressions in the rotenone mouse model of PD confirmed the compromised autophagy pathway, consequently increasing the aggregation of misfolded protein α-syn. Whereas, curcumin treatment-enhanced autophagy-mediated clearance of misfolded α-syn proteins by increasing the LC3-II expression and blocked apoptotic cascade. Curcumin administration upregulated the Nrf2 expression and normalized the Nrf2-Keap1 pathway, which justifies the improved anti-oxidative activity. Therefore, the findings reveal that curcumin is a Nrf2-inducer and is endowed with neuroprotective potential, which may prove to be a potential candidate for the anti-Parkinson's disease treatment therapy.

Corrigendum: Effect of chlorogenic acid supplementation in MPTP-intoxicated mouse.

[This corrects the article DOI: 10.3389/fphar.2018.00757.].

Oleuropein confers neuroprotection against rotenone-induced model of Parkinson's disease via BDNF/CREB/Akt pathway.

Major pathological features of Parkinson's disease (PD) include increase in oxidative stress leading to the aggregation of α-synuclein, mitochondrial dysfunction and apoptosis of dopaminergic neurons. In addition, downregulation of the expression of neurotrophic factors like-Brain Derived Neurotrophic Factor (BDNF) is also involved in PD progression. There has been a lot of interest in trophic factor-based neuroprotective medicines over the past few decades to treat PD symptoms. Rotenone, an insecticide, inhibits the mitochondrial complex I causing overproduction of ROS, oxidative stress, and aggregation of α-synuclein. It has been shown that BDNF and Tropomyosin receptor kinase B (TrkB) interaction initiates the regulation of neuronal cell development and differentiation by the serine/threonine protein kinases like Akt and GSK-3ß. Additionally, Transcription factor CREB (cAMP Response Element-binding protein) also determines the gene expression of BDNF. The homeostasis of these signalling cascades is compromised with the progression of PD. Therefore, maintaining the equilibrium of these signalling cascades will delay the onset of PD. Oleuropein (OLE), a polyphenolic compound present in olive leaves has been documented to cross blood brain barrier and shows potent antioxidative property. In the present study, the dose of 8, 16 and 32 mg/kg body weight (bwt) OLE was taken for dose standardisation. The optimised doses of 16 and 32 mg/kg bwt was found to be neuroprotective in Rotenone induced PD mouse model. OLE improves motor impairment and upregulate CREB regulation along with phosphorylation of Akt and GSK-3ß in PD mouse. In addition, OLE also reduces the mitochondrial dysfunction by activation of enzyme complexes and downregulates the proapoptotic markers in Rotenone intoxicated mouse model. Overall, our study suggests that OLE may be used as a therapeutic agent for treatment of PD by regulating BDNF/CREB/Akt signalling pathway.

Wheatgrass extract imparts neuroprotective actions against scopolamine-induced amnesia in mice.

The rich and diverse phytoconstituents of wheatgrass have established it as a natural antioxidant and detoxifying agent. The anti-inflammatory potential of wheatgrass has been studied extensively. However, the neuroprotective potential of wheatgrass has not been studied in depth. In this study, we investigated the neuroprotective response of wheatgrass against age-related scopolamine-induced amnesia in mice. Scopolamine is an established anticholinergic drug that demonstrates the behavioural and molecular characteristics of Alzheimer's disease. In the current study, wheatgrass extracts (prepared from 5 and 7 day old plantlets) were administered to scopolamine-induced memory deficit mice. The Morris water maze (MWM) and Y-maze tests demonstrated that wheatgrass treatment improves the behavior and simultaneously enhances the memory of amnesic mice. We further evaluated the expression of neuroinflammation related genes and proteins in the hippocampal region of mice. Wheatgrass significantly upregulated the mRNA and protein expression of neuroprotective markers such as BDNF and CREB in scopolamine-induced mice. Simultaneously, wheatgrass also downregulated the expression of inflammatory markers such as TNF-α and tau genes in these mice. The treatment of scopolamine-induced memory impaired mice with wheatgrass resulted in an elevation in the level of the phosphorylated form of ERK and Akt proteins. Wheatgrass treatment of mice also regulated the phosphorylation of tau protein and simultaneously prevented its aggregation in the hippocampal region of the brain. Overall, this study suggests the therapeutic potential of wheatgrass in the treatment of age-related memory impairment, possibly through the involvement of ERK/Akt-CREB-BDNF pathway and concomitantly ameliorating the tau-related pathogenesis.

Neuroprotection by Mucuna pruriens in Neurodegenerative Diseases.

The medicinal plant Mucuna pruriens (Fabaceae) is widely known for its anti-oxidative and anti-inflammatory properties. It is a well-established drug in Ayurveda and has been widely used for the treatment of neurological disorders and male infertility for ages. The seeds of the plant have potent medicinal value and its extract has been tested in different models of neurodegenerative diseases, especially Parkinson's disease (PD). Apart from PD, Mucuna pruriens is now being studied in models of other nervous systems disorders such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and stroke because of its neuroprotective importance. This review briefly discusses the pathogenesis of PD, AD, ALS and stroke. It aims to summarize the medicinal importance of Mucuna pruriens in treatment of these diseases, and put forward the potential targets where Mucuna pruriens can act for therapeutic interventions. In this review, the effect of Mucuna pruriens on ameliorating the neurodegeneration evident in PD, AD, ALS and stroke is briefly discussed. The potential targets for neuroprotection by the plant are delineated, which can be studied further to validate the hypothesis regarding the use of Mucuna pruriens for the treatment of these diseases.

Unraveling the Neuroprotective Effect of Tinospora cordifolia in a Parkinsonian Mouse Model through the Proteomics Approach.

Stress-induced dopaminergic (DAergic) neuronal death in the midbrain region is the primary cause of Parkinson's disease (PD). Following the discovery of l-dopa, multiple drugs have been developed to improve the lifestyle of PD patients; however, none have been suitable for clinical use due to their multiple side effects. Tinospora cordifolia has been used in traditional medicines to treat neurodegenerative diseases. Previously, we reported the neuroprotective role of Tc via inhibition of NF-κB-associated proinflammatory cytokines against MPTP-intoxicated Parkinsonian mice. In the present study, we investigated the neuroprotective molecular mechanism of Tc in a rotenone (ROT)-intoxicated mouse model, using a proteomics approach. Mice were pretreated with Tc extract by oral administration, followed by ROT intoxication. Behavioral tests were performed to check motor functions of mice. Protein was isolated, and label-free quantification (LFQ) was carried out to identify differentially expressed protein (DEP) in control vs PD and PD vs treatment groups. Results were validated by qRT-PCR with the expression of target genes correlating with the proteomics data. In this study, we report 800 DEPs in control vs PD and 133 in PD vs treatment groups. In silico tools demonstrate significant enrichment of biochemical and molecular pathways with DEPs, which are known to be important for PD progression including mitochondrial gene expression, PD pathways, TGF-ß signaling, and Alzheimer's disease. This study provides novel insights into the PD progression as well as new therapeutic targets. More importantly, it demonstrates that Tc can exert therapeutic effects by regulating multiple pathways, resulting in neuroprotection.

Epigenetic Modulation in Parkinson's Disease and Potential Treatment Therapies.

In the recent past, huge emphasis has been given to the epigenetic alterations of the genes responsible for the cause of neurological disorders. Earlier, the scientists believed somatic changes and modifications in the genetic makeup of DNA to be the main cause of the neurodegenerative diseases. With the increase in understanding of the neural network and associated diseases, it was observed that alterations in the gene expression were not always originated by the change in the genetic sequence. For this reason, extensive research has been conducted to understand the role of epigenetics in the pathophysiology of several neurological disorders including Alzheimer's disease, Parkinson's disease and, Huntington's disease. In a healthy person, the epigenetic modifications play a crucial role in maintaining the homeostasis of a cell by either up-regulating or down-regulating the genes. Therefore, improved understanding of these modifications may provide better insight about the diseases and may serve as potential therapeutic targets for their treatment. The present review describes various epigenetic modifications involved in the pathology of Parkinson's Disease (PD) backed by multiple researches carried out to study the gene expression regulation related to the epigenetic alterations. Additionally, we will briefly go through the current scenario about the various treatment therapies including small molecules and multiple phytochemicals potent enough to reverse these alterations and the future directions for a better management of PD.

Neuroprotection of Rotenone-Induced Parkinsonism by Ursolic Acid in PD Mouse Model.

BACKGROUND: Parkinson's Disease (PD) is characterized by both motor and non-motor symptoms. The presynaptic neuronal protein, α-Synuclein, plays a pivotal role in PD pathogenesis and is associated with both genetic and sporadic origin of the disease. Ursolic Acid (UA) is a well-known bioactive compound found in various medicinal plants, widely studied for its anti-inflammatory and antioxidant activities. OBJECTIVE: In this research article, the neuroprotective potential of UA has been further explored in the Rotenone-induced mouse model of PD. METHODS: To investigate our hypothesis, we have divided mice into 4 different groups, control, drug only control, Rotenone-intoxicated group, and Rotenone-intoxicated mice treated with UA. After the completion of dosing, behavioral parameters were estimated. Then mice from each group were sacrificed and the brains were isolated. Further, the biochemical tests were assayed to check the balance between the oxidative stress and endogenous anti-oxidants; and TH (Tyrosine Hydroxylase), α-Synuclein, Akt (Serine-threonine protein kinase), ERK (Extracellular signal-regulated kinase) and inflammatory parameters like Nuclear Factor-κB (NF-κB) and Tumor Necrosis Factor- α (TNF-α) were assessed using Immunohistochemistry (IHC). Western blotting was also done to check the expressions of TH and α-Synuclein. Moreover, the expression levels of PD related genes like α-Synuclein, ß-Synuclein, Interleukin-1ß (IL-1ß), and Interleukin-10 (IL-10) were assessed by using Real-time PCR. RESULTS: The results obtained in our study suggested that UA significantly reduced the overexpression of α-Synuclein and regulated the phosphorylation of survival-related kinases (Akt and ERK) apart from alleviating the behavioral abnormalities and protecting the dopaminergic neurons from oxidative stress and neuroinflammation. CONCLUSION: Thus, our study shows the neuroprotective potential of UA, which can further be explored for possible clinical intervention.

Neuroprotective Effect of Chlorogenic Acid on Mitochondrial Dysfunction-Mediated Apoptotic Death of DA Neurons in a Parkinsonian Mouse Model.

Mitochondrial dysfunction and oxidative stress characterize major factors involved in the activation of complex processes corresponding to apoptosis-mediated neuronal senescence of dopaminergic neurons (DA) in Parkinson's disease (PD). Here, we evaluated the molecular mechanisms participating in the treatment of a 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine- (MPTP-) intoxicated PD mouse model in response to chlorogenic acid (CGA). The results indicate that CGA treatment significantly improved the motor coordination of the MPTP-intoxicated mice. CGA also alleviated the fall in activity of mitochondrial complexes I, IV, and V in accordance with ameliorating the level of superoxide dismutase and mitochondrial glutathione in the midbrain of MPTP-induced mice. CGA inhibited the activation of proapoptotic proteins including Bax and caspase-3, while elevating the expression of antiapoptotic protein like Bcl-2 consequently preventing the MPTP-mediated apoptotic cascade. The study also revealed the improved phosphorylation state of Akt, ERK1/2, and GSK3ß which was downregulated as an effect of MPTP toxicity. Our findings signify that CGA may possess pharmacological properties and contribute to neuroprotection against MPTP induced toxicity in a PD mouse model associated with phosphorylation of GSK3ß via activating Akt/ERK signalling in the mitochondrial intrinsic apoptotic pathway. Thus, CGA treatment may arise as a potential therapeutic candidate for mitochondrial-mediated apoptotic senescence of DA neurons in PD.

NF-κB-Mediated Neuroinflammation in Parkinson's Disease and Potential Therapeutic Effect of Polyphenols.

Different animal and human studies from last two decades in the case of Parkinson's disease (PD) have concentrated on oxidative stress due to increased inflammation and cytokine-dependent neurotoxicity leading to induction of dopaminergic (DA) degeneration pathway in the nigrostriatal region. Chronic inflammation, the principle hallmark of PD, forms the basis of neurodegeneration. Aging in association with activation of glia due to neuronal injury, perhaps because of immune alterations and genetic predispositions, leads to deregulation of inflammatory pathways premising the onset of PD. A family of inducible transcription factors, nuclear factor-κB (NF-κB), is found to show expression in various cells and tissues, such as microglia, neurons, and astrocytes which play an important role in activation and regulation of inflammatory intermediates during inflammation. Both canonical and non-canonical NF-κB pathways are involved in the regulation of the stimulated cells. During the prodromal/asymptomatic stage of age-associated neurodegenerative diseases (i.e., PD and AD), chronic neuroinflammation may act silently as the driver of neuronal dysfunction. Though research has provided an insight over age-related neurodegeneration in PD, elaborative role of NF-κB in neuroinflammation is yet to be completely understood and thus requires more investigation. Polyphenols, a group of naturally occurring compound in medicinal plants, have gained attention because of their anti-oxidative and anti-neuroinflammatory properties in neurodegenerative diseases. In this aspect, this review highlights the role of NF-κB and the possible therapeutic roles of polyphenols in NF-κB-mediated neuroinflammation in PD.

Quality Control in Huntington's Disease: a Therapeutic Target.

Huntington's disease (HD) is a fatal autosomal dominantly inherited brain disease caused by excessively expanded CAG repeats in gene which encodes huntingtin protein. These abnormally encoded huntingtin proteins and their truncated fragments result in disruption of cellular quality mechanism ultimately triggering neuronal death. Despite great efforts, a potential causative agent leading to genetic mutation in HTT, manifesting the neurons more prone to oxidative stress, cellular inflammation, energy depletion and apoptotic death, has not been established yet. Current scenario concentrates on symptomatic pathologies to improvise the disease progression and to better the survival. Most of the therapeutic developments have been converged to rescue the protein homeostasis. In HD, abnormal expansion of glutamine repeats in the protein huntingtin leads to toxic aggregation of huntingtin which in turn impairs the quality control mechanism of cells through damaging the machineries involved in removal of aggregated abnormal protein. Therapeutic approaches to improve the efficiency of aggregate clearance through quality control mechanisms involve protein folding machineries such as chaperones and protein degradation machineries such as proteasome and autophagy. Also, to reduce protein aggregation by enhancing proper folding, to degrade and eliminate the aggregates are suggested to negatively regulate the HD progression associated with the disruption of protein homeostasis. This review focuses on the collection of therapeutic strategies targeting enhancement of protein quality control activity to delay the HD pathogenesis.

Neuroprotective effects of Withania somnifera in BPA induced-cognitive dysfunction and oxidative stress in mice.

BACKGROUND: Bisphenol A (BPA), a major endocrine disruptor and a xenobiotic compound is used abundantly in the production of polycarbonate plastics and epoxy resins. Human exposure to this compound is primarily via its leaching from the protective internal epoxy resin coatings of containers into the food and beverages. In addition, the plastics used in dental prostheses and sealants also contain considerable amount of BPA and have a high risk of human exposure. Since it is a well-known endocrine disruptor and closely mimics the molecular structure of human estrogen thereby impairing learning and memory. Withania somnifera (Ws), commonly known as Ashwagandha is known for its varied therapeutic uses in Ayurvedic system of medicine. The present study was undertaken to demonstrate the impairment induced by BPA on the spatial learning, working memory and its alleviation by Ws in Swiss albino mice. The study was conducted on thirty Swiss albino mice, randomly distributed among three groups: control, BPA and BPA + Ws. The behavioral recovery after treatment with Ws was investigated using the Y-maize and Morris water maize test. Whereas, for the estimation of recovery of NMDA receptor which is related to learning and memory in hippocampus region by western blot and immunohistochemistry. Furthermore, the oxidative stress and antioxidant level was assessed by biochemical tests like MDA, SOD and catalase. RESULTS: The study revealed that administration of Ws alleviated the behavioral deficits induced by BPA. Alongside, Ws treatment reinstated the number of NMDA receptors in hippocampus region and showed anti-oxidative property while ameliorating the endogenous anti-oxidant level in the brain. CONCLUSION: These findings suggest that Ws significantly ameliorates the level of BPA intoxicated oxidative stress thereby potentially treating cognitive dysfunction which acts as the primary symptom in a number of neurodegenerative diseases.

Anti-inflammatory Activity of Ursolic Acid in MPTP-Induced Parkinsonian Mouse Model.

Neuroinflammation plays an important role in the progression of Parkinson's disease (PD) and hence may represent a target for treatment. The drugs used currently for PD only provide symptomatic relief and have adverse effects in addition to their inability in preventing degeneration of neurons. Flavonoids show potent antioxidant and anti-inflammatory activities which is very valuable for the health of human beings. Thus, in the present study, we have tried to explore the anti-inflammatory activity of orally given ursolic acid (UA) (25 mg/kg bwt), a pentacyclic triterpenoid in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model. Significant severe oxidative stress and biochemical alterations have been seen in Parkinsonian mice after MPTP intoxication. Whereas, UA administration has significantly rescued the harmful consequence of MPTP intoxication. Ionized calcium-binding adaptor molecule 1 (Iba1), tumor necrosis factor-alpha (TNF-α), and nuclear transcription factor-κB (NF-κB) were seen to be altered in the substantia nigra pars compacta (SNpc) of MPTP-intoxicated mice through immunohistochemical studies. The changes in the expression level of these parameters primarily suggest increased inflammatory responses in MPTP-intoxicated mice as compared with the control. However, UA have significantly reduced these inflammatory parameters (Iba1 and TNF-α) along with transcription factor NF-κB, which regulates these inflammatory parameters and thus have inhibited MPTP-induced neuroinflammation. The immunoreactivity of tyrosine hydroxylase (TH) was considerably increased by UA treatment in the SNpc of Parkinsonian mice. The neuroinflammation and neurodegeneration along with impairments in biochemical and behavioral parameters were found to be reversed on treatment with UA. Thus, UA has shown potent anti-inflammatory activity by preventing the degeneration of dopaminergic neurons from MPTP-induced Parkinsonian mice.

The Role of PI3K/Akt and ERK in Neurodegenerative Disorders.

Disruption of Akt and Erk-mediated signal transduction significantly contributes in the pathogenesis of various neurodegenerative diseases (NDs), such as Parkinson's disease, Alzheimer's diseases, Huntington's disease, and many others. These regulatory proteins serve as the regulator of cell survival, motility, transcription, metabolism, and progression of the cell cycle. Therefore, targeting Akt and Erk pathway has been proposed as a reasonable approach to suppress ND progression. This review has emphasized on involvement of Akt/Erk cascade in the neurodegeneration. Akt has been reported to regulate neuronal toxicity through its various substrates like FOXos, GSK3ß, and caspase-9 etc. Akt is also involved with PI3K in signaling pathway to mediate neuronal survival. ERK is another kinase which also regulates proliferation, differentiation, and survival of the neural cell. There has also been much progress in developing a therapeutic molecule targeting Akt and Erk signaling. Therefore, improved understanding of the molecular mechanism behind the regulatory aspect of Akt and Erk networks can make strong impact on exploration of the neurodegenerative disease pathogenesis.

Tinospora cordifolia Suppresses Neuroinflammation in Parkinsonian Mouse Model.

Parkinson's disease (PD), a neurodegenerative central nervous system disorder, is characterised by progressive loss of nigrostriatal neurons in basal ganglia. Previous studies regarding PD have suggested the role of oxidative stress along with neuroinflammation in neurodegeneration. Accordingly, our study explore the anti-inflammatory activity of Tinospora cordifolia aqueous extract (TCAE) in 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP)-intoxicated Parkinsonian mouse model. MPTP-intoxicated mice showed significant behavioral and biochemical abnormalities which were effectively reversed by TCAE. It is evident that TCAE inhibits the MPTP-intoxicated Nuclear factor-κB (NF-κB) activation and its associated pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) from immunohistochemistry and Western blot analysis. In MPTP-intoxicated mice, microglial and astroglial-specific inflammatory markers, ionized calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP), respectively were increased while were significantly reduced in TCAE treatment. Expression of pro-inflammatory cytokine genes, TNF-α, Interleukin-12 (IL-12) and Interleukin-1ß (IL-1ß) were found to be upregulated in MPTP-intoxicated mice, whereas TCAE treatment restored their levels. Additionally, anti-inflammatory factor Interleukin-10 (IL-10) gene was found to be downregulated in MPTP-intoxicated mice which were significantly restored by TCAE treatment. Tyrosine hydroxylase (TH) expression was reduced in MPTP-intoxicated mice, while its expression was significantly increased in TCAE-treated group. Our result strongly suggests that T. cordifolia protects dopaminergic neurons by suppressing neuroinflammation in MPTP-induced Parkinsonian mouse model.

Effect of Chlorogenic Acid Supplementation in MPTP-Intoxicated Mouse.

Oxidative stress and neuroinflammation play a key role in dopaminergic (DA) neuronal degeneration, which results in the hindrance of normal ongoing biological processes in the case of Parkinson's disease. As shown in several studies, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, different behavioral parameters have suggested motor impairment and damage of antioxidant defence. Thus, some specific biological molecules found in medicinal plants can be used to inhibit the DA neuronal degeneration through their antioxidant and anti-inflammatory activities. With this objective, we studied chlorogenic acid (CGA), a naturally occurring polyphenolic compound, for its antioxidant and anti-inflammatory properties in MPTP-intoxicated mice. We observed significant reoccurrence of motor coordination and antioxidant defence on CGA supplementation, which has been in contrast with MPTP-injected mice. Moreover, in the case of CGA-treated mice, the enhanced expression of tyrosine hydroxylase (TH) within the nigrostriatal region has supported its beneficial effect. The activation of glial cells and oxidative stress levels were also estimated using inducible nitric oxide synthase (iNOS) and glial fibrillary acidic protein (GFAP) immunoreactivity within substantia nigra (SN) and striatum of MPTP-injected mice. Administration of CGA has prevented the neuroinflammation in SN by regulating the nuclear factor-κB expression in the MPTP-induced group. The significant release of certain pro-inflammatory mediators such as tumor necrosis factor-α and interleukin (IL)-1ß has also been inhibited by CGA with the enhanced expression of anti-inflammatory cytokine IL-10. Moreover, reduced GFAP staining within the nigrostriatal region has supported the fact that CGA has significantly helped in the attenuation of astrocyte activation. Hence, our study has shown that CGA supplementation shows its therapeutic ability by reducing the oxidative stress and neuroinflammation in MPTP-intoxicated mice.