Obesity aggravates neuroinflammatory and neurodegenerative effects of bisphenol A in female rats.

Bisphenol A (BPA), a common plasticizer, is categorized as a neurotoxic compound. Its impact on individuals exhibits sex-linked variations. Several biological and environmental factors impact the degree of toxicity. Moreover, nutritional factors have profound influence on toxicity outcome. BPA has been demonstrated to be an obesogen. However, research on the potential role of obesity as a confounding factor in BPA toxicity is lacking. We studied the neurodegenerative effects in high-fat diet (HFD)-induced obese female rats after exposure to BPA (10 mg/L via drinking water for 90 days). Four groups were taken in this study - Control, HFD, HFD + BPA and BPA. Cognitive function was evaluated through novel object recognition (NOR) test. Inflammatory changes in brain, and changes in hormonal level, lipid profile, glucose tolerance, oxidative stress, and antioxidants were also determined. HFD + BPA group rats showed a significant decline in memory function in NOR test. The cerebral cortex (CC) of the brain showed increased neurodegenerative changes as measured by microtubule-associated protein-2 (MAP-2) accompanied by histopathological confirmation. The increased level of neuroinflammation was demonstrated by microglial activation (Iba-1) and protein expression of nuclear factor- kappa B (NF-КB) in the brain. Obesity also caused significant (p < 0.05) increase in lipid peroxidation accompanied by reduced activities of antioxidant enzymes (glutathione S-transferase, catalase and glutathione peroxidase) and decrease in reduced-glutathione (p < 0.05) when compared to non-obese rats with BPA treatment. Overall, study revealed that obesity serves as a risk factor in the toxicity of BPA which may exacerbate the progression of neurological diseases.

Impact of advance care planning and end-of-life conversations on patients with cancer: An integrative review of literature.

PURPOSE: The purpose was to review published articles to examine the impact of advance care planning (ACP) and end-of-life (EOL) conversations on patients with cancer, and aimed to compare the findings for congruency with the goals of ACP. DESIGN AND METHOD: The study was guided by Whittemore and Knafl's integrative review methodology. Articles published between 2015 to 2020 were identified through electronic databases. The search included: Cumulative Index for Nursing Allied Health Literature (CINAHL), PubMed, MEDLINE-Ovid, and MEDLINE full text, and using the MeSH terms. Two hundred and five (205) articles were identified and screened for eligibility, and 15 articles were appraised. FINDINGS: The fifteen (15) articles that met the inclusion criteria included five (5) qualitative, eight (8) quantitative, and two (2) mixed methods. The review analysis revealed six themes emerged in three categories: cancer patients' experience with advance care planning (1) patients' prognostic awareness, (2) decision making; cancer patients' perceived outcomes with advance care planning (3) patient-provider relationship, (4) concordance in care based on goals, and cancer patients' propositions related to advance care planning, (5) timings of advance care planning discussions, and (6) support during ACP and/or EOL conversations. CONCLUSION: ACP and EOL conversations play a critical role in cancer patients' awareness of their disease and prognosis and help them in making end-of-life care decisions. CLINICAL RELEVANCE: There exists a need for earlier ACP and EOL conversations with cancer patients with emotional support during these conversations.

Tempol (4-hydroxy tempo) protects mice from cisplatin-induced acute kidney injury via modulation of expression of aquaporins and kidney injury molecule-1.

Tempol (4-hydroxy tempo), a pleiotropic antioxidant is reported to afford protection against cisplatin (CP)-induced nephrotoxicity. However, molecular mechanisms of action of tempol in improving the renal function in CP-induced nephrotoxicity are not fully understood. We investigated the attenuating effect of tempol against CP-induced alterations in kidney injury molecule-1 (KIM-1) and aquaporins (AQPs) in mice. Tempol (100 mg/kg, po) pretreatment with CP (20 mg/kg ip) showed restoration in renal function markers including electrolytes. CP treatment upregulated mRNA expression of KIM-1 and downregulated AQP and arginine vasopressin (AVP) expression which was attenuated by tempol. Immunoblotting analysis revealed that CP-induced alterations in KIM-1 and AQP expression were restored by tempol. Immunofluorocense study also showed restorative effect of tempol on the expression of AQP2 in CP-treated mice. In conclusion, this study provides experimental evidence that tempol resolved urinary concentration defect by the restoration of AQP, AVP and KIM-1 levels indicating a potential use of tempol in ameliorating the AKI in cancer patients under the treatment with CP.

Downregulation of ATF-4 Attenuates the Endoplasmic Reticulum Stress-Mediated Neuroinflammation and Cognitive Impairment in Experimentally Induced Alzheimer's Disease Model.

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-ß (Aß)(1-42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B (NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aß accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress-mediated inflammation in cognitive impairment. Administration of Aß(1-42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aß(1-42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress-mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression.

Protective effect of rosmarinic acid on the transmembrane transporter Ctr1 expression in cisplatin-treated mice.

AIMS: Cisplatin (cis-diamminedichloroplatinum(II), CP) is a platinum-based anticancer drug widely used in the treatment of solid malignancies. However, its side effects, particularly nephrotoxicity, are limiting factors in its clinic use. Rosmarinic acid (RA), a natural antioxidant compound, is reported to attenuate oxidative stress and associated pathophysiological outcomes. Our study aimed to explore the protective effect of RA against CP-induced acute kidney injury (AKI). MATERIALS AND METHODS: We investigated the effect of RA at the dose of 100 mg/kg on AKI induced by CP (20 mg/kg) in mice. Various parameters of nephrotoxicity such as levels of serum electrolytes, albumin, and globulin were measured using standardized methods. Besides, a specific biomarker of damage to proximal tubular cells, kidney injury molecule-1 (Kim-1), was measured in the serum by ELISA. mRNA expression of Kim-1 and a transmembrane transporter, copper transporter 1 (Ctr1), was analyzed by quantitative reverse transcriptase-polymerase chain reaction. CTR1 expression was also analyzed by western blot technique. RESULTS: RA treatment restored the downregulated CTR1 , a renal transmembrane transporter in CP-treated mice. It was accompanied by a reduction in the level of serum albumin and globulin. Serum electrolytes such as Na+, K+, and Ca2+ in CP-treated mice were found to be restored with RA treatment. Moreover, RA also significantly downregulated the increased expression of nephrotoxicity biomarker KIM-1. CONCLUSIONS: Overall, RA proved to be an effective nephroprotective compound which afforded protection at cellular and subcellular levels with an appreciable modulatory effect on a transmembrane transporter.

Astrocyte activation: a key step in rotenone induced cytotoxicity and DNA damage.

Astrocytes are the most abundant glial cells, which provide metabolic support for neurons. Rotenone is a botanical pesticide of natural origin, known to exhibit neurotoxic potential via inhibition of mitochondrial complex-I. This study was carried out to explore the effect of rotenone on C6 cells. The cell line C6 derived from rat glioma cells represents astrocyte-like cell. C6 cells were treated with rotenone (0.1, 1 and 10 µM) for 4 h. The effect of rotenone was studied on cell survival (MTT reduction and PI uptake); free radicals (ROS and RNS) and DNA damage (comet assay and Hoechst staining). The glial cell activation and apoptotic cell death was evaluated by expression of Glial fibrillary acidic protein (GFAP) and caspase-3 respectively. The treatment with rotenone resulted in decreased cell survival and increased free radical generation. Altered nuclear morphology and DNA damage were evident following rotenone treatment in Hoechst staining and Comet assay. Rotenone elevated expression of GFAP and caspase-3 that indicates glial cell activation and apoptosis, respectively. We further studied the effect of melatonin, an antioxidant, on the observed toxic effects. Co-incubation of antioxidant, melatonin (300 µM), significantly suppressed rotenone induced above-mentioned effects in C6 cells. Inhibitory effects of melatonin suggest that free radicals play a major role in rotenone induced astrocyte activation and cellular toxicity leading to apoptosis of astroglial cells.

Rotenone-induced apoptosis and role of calcium: a study on Neuro-2a cells.

Rotenone causes cytotoxicity in astrocytic cell culture by glial activation, which is linked to free radical generation. The present study is an investigation to explore whether rotenone could also cause cellular toxicity in mouse neuroblastoma cells (Neuro-2a) under treatment similar to astroglial cells. The effect of rotenone (0.1, 1, and 10 µM) on mitochondrial dehydrogenase enzyme activity by MTT reduction assay, PI uptake, total reactive oxygen species (ROS)/superoxide levels, nitrite levels, extent of DNA damage (by comet assay), and nuclear morphological alteration by Hoechst staining was studied. Caspase-3 and Ca⁺²/calmodulin-dependent protein kinase II (CaMKIIα) gene expression was determined to evaluate the apoptotic cell death and calcium kinase, respectively. Calcium level was estimated fluorometrically using fura-2A stain. Rotenone decreased mitochondrial dehydrogenase enzyme activity and generated ROS, superoxide, and nitrite. Rotenone treatment impaired cell intactness and nuclear morphology as depicted by PI uptake and chromosomal condensation of Neuro-2a cells, respectively. In addition, rotenone resulted in increased intracellular Ca⁺² level, caspase-3, and CaMKIIα expression. Furthermore, co-exposure of melatonin (300 µM), an antioxidant to cell culture, significantly suppressed the rotenone-induced decreased mitochondrial dehydrogenase enzyme activity, elevated ROS and RNS. However, melatonin was found ineffective to counteract rotenone-induced increased PI uptake, altered morphological changes, DNA damage, elevated Ca⁺², and increased expression of caspase-3 and CaMKIIα. The study indicates that intracellular calcium rather than oxidative stress is a major factor for rotenone-induced apoptosis in neuronal cells.

mRNA expression and protein-protein interaction (PPI) network analysis of adrenal steroidogenesis in response to exposure to phthalates in rats.

Phthalate esters such as di-butyl phthalate (DBP) and di-ethyl hexyl phthalate (DEHP) used in personal care and consumer products and medical devices have potential to affect human health. We studied the effect of DBP and DEHP on critical enzymes of glucocorticoid biosynthesis pathway in the adrenal gland and pro-inflammatory cytokines in the serum in male Wistar rats. DEHP and DBP treatment altered the mRNA expression of enzymes of glucocorticoid biosynthesis pathway accompanied by a reduction in glucocorticoid production and elevation in the level of glucocorticoid regulated pro-inflammatory cytokines indicating a cascading effect of phthalates. The analysis of PPI (protein - protein interaction) network involving Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) of enzymes through STRING database revealed that all the proteins have the maximum level of interaction with the selected number of proteins. The STRING database analysis together with in vivo data indicates the potential effects of phthalates on various targets of steroidogenesis pathway with a global biological impact.

NLRP3 inflammasome in rosmarinic acid-afforded attenuation of acute kidney injury in mice.

Cisplatin (CP) is a well-known anticancer drug used to effectively treat various kinds of solid tumors. CP causes acute kidney injury (AKI) and unfortunately, there is no therapeutic approach in hand to prevent AKI. Several signaling pathways are responsible for inducing AKI which leads to inflammation in proximal convoluted tubule cells in the kidney. Furthermore, the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is involved in the CP-induced AKI. In this study, we investigated therapeutic effects of rosmarinic acid (RA) against inflammation-induced AKI. RA was orally administered at the dose of 100 mg/kg for two consecutive days after 24 h of a single injection of CP at the dose of 20 mg/kg administered intraperitoneally in Swiss albino male mice. Treatment of RA inhibited the activation of NLRP3 signaling pathway by blocking the activated caspase-1 and downstream signal molecules such as IL-1ß and IL18. CP activated HMGB1-TLR4/MyD88 axis was also found to be downregulated with the RA treatment. Activation of nuclear factor-κB and elevated protein expression of cyclooxygenase-2 (COX-2) were also found to be downregulated in RA-treated animals. Alteration of early tubular injury biomarker, kidney injury molecule-1 (KIM-1), was found to be subsided in RA-treated mice. RA has been earlier reported for antioxidant and anti-inflammatory properties. Our findings show that blocking a critical step of inflammasome signaling pathway by RA treatment can be a novel and beneficial approach to prevent the CP-induced AKI.

Management of Adverse Events in Early Clinical Trials by Advanced Practice Providers in the Outpatient Setting: The University of Texas MD Anderson Cancer Center Experience.

Background: Advanced practice providers (APPs) play important roles in enrolling, educating, and caring for patients in clinical trials. However, much remains unknown about the role of APPs in managing adverse events (AEs) in early (phase I to II) clinical trials. In this study, we assessed the outpatient management of grade 3 to 4 AEs by APPs in early trials and characterized the workflow of our APP Phase I to II Fast Track (FT) Clinic. Patients and Methods: We retrospectively reviewed records of patients with advanced or metastatic solid tumors enrolled in phase I to II clinical trials who were seen by APPs from September 2017 to August 2018 in the APP phase I to II FT clinic in the Department of Investigational Cancer Therapeutics. Results: A total of 808 patients enrolled in 159 clinical trials were seen in 2,697 visits (median 3 visits per patient; range 1-28) by 10 APPs. Treatment was interrupted in 6.9% of visits, and grade 3 to 4 AEs were seen in 5.4% of visits; however, patients from 1.4% of visits were sent to the emergency center (EC) and/or admitted. Patients referred to the EC and/or admitted were more likely to have baseline hypoalbuminemia, high lactate dehydrogenase, and poor Eastern Cooperative Oncology Group performance status (i.e., ECOG > 1; p < .001). There were no associations between EC referral and gender, APP years of experience, or type of treatment. Conclusions: The APP Phase I to II FT Clinic has an important role in the management of AEs by APPs in early clinical trials in the outpatient setting, potentially avoiding EC visits and admissions.

A study to evaluate the effect of nootropic drug-piracetam on DNA damage in leukocytes and macrophages.

Piracetam is a nootropic drug that protects neurons in neuropathological and age-related diseases and the activation and modulation of peripheral blood cells in patients with neuropathological conditions is well known. Therefore, in the present study, in vivo, ex vivo, and in vitro tests were conducted to investigate the effect of piracetam on leukocytes and macrophages. Lipopolysaccharide (LPS) causes oxidative DNA damage; thus, in the present study, LPS was used as a tool to induce DNA damage. In vivo experiments were conducted on Sprague Dawley rats, and piracetam (600mg/kg, oral) was provided for five consecutive days. On the fifth day, a single injection of LPS (10mg/kg, i.p.) was administered. Three hours after LPS injection, blood leukocytes and peritoneal macrophages were collected and processed, and a variety of different assays were conducted. Ex vivo treatments were performed on isolated rat blood leukocytes, and in vitro experiments were conducted on rat macrophage cell line J774A.1. Cell viability and the level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and DNA damage were estimated in untreated (control) and piracetam-, LPS- and LPS+piracetam-treated leukocytes and macrophages. In vivo experiments revealed that rats pretreated with piracetam were significantly protected against LPS-induced increases in ROS levels and DNA damage. Ex vivo isolated leukocytes and J774A.1 cells treated with LPS exhibited augmented ROS levels and DNA damage, which were attenuated with piracetam treatment. Thus, the present study revealed the salutary effect of piracetam against LPS-induced oxidative stress and DNA damage in leukocytes and macrophages.

Astrocytes and microglia: responses to neuropathological conditions.

Activated astrocytes and microglia, hallmark of neurodegenerative diseases release different factors like array of pro and anti-inflammatory cytokines, free radicals, anti-oxidants, and neurotrophic factors during neurodegeneration which further contribute to neuronal death as well as in survival mechanisms. Astrocytes act as double-edged sword exerting both detrimental and neuroprotective effects while microglial cells are attributed more in neurodegenerative mechanisms. The dual and insufficient knowledge about the precise role of glia in neurodegeneration showed the need for further investigations and thorough review of the function of glia in neurodegeneration. In this review, we consolidate and categorize the glia-released factors which contribute in degenerative and protective mechanisms during neuropathological conditions.

Advance Care Planning and End-Of-Life Communications: Practical Tips for Oncology Advanced Practitioners.

Advance care planning discussions ensure patients' values and goals of care, including the freedom to choose their place of death, are respected. The benefits of advance care planning and early end-of-life care discussions are often delayed, as these discussions are not initiated early in patients' cancer trajectories. As a result, patients' wishes often remain unknown until the last phase of their life. Evidence suggests that many patients inappropriately receive aggressive treatment near the end of life, which leads to higher resource utilization, decreased quality of life, and increased cost. The purpose of this article is to provide practical tips to the oncology advanced practitioner on initiating advance care planning and end-of-life care discussions with patients and their families or caregivers.

Advance Care Planning: Advanced Practice Provider-Initiated Discussions and Their Effects on Patient-Centered End-of-Life Care.

BACKGROUND: Advance care planning (ACP) is an ongoing process of communication involving patients, family members, and caregivers on one side and healthcare providers on the other to establish values, goals, and preferences for future care, along with discussions concerning end-of-life care options. Advance directives promote patient autonomy and provide written documentation of a patient's wishes for future care. OBJECTIVES: This quality improvement project aimed to determine if ACP discussions initiated by an advanced practice provider (APP) would enhance patient-centered end-of-life care. METHODS: This study involved retrospective data collection of 20 inpatients and 20 outpatients without a scanned advance directive in the electronic health record at the time of admission or clinic visit, as well as an ACP intervention by an APP. FINDINGS: APPs can initiate ACP discussions with patients with cancer, which may assist in their understanding of ACP, resulting in completion of the advance directive documents and a change in their code (resuscitation) status.

Involvement of endoplasmic reticulum stress in amyloid ß (1-42)-induced Alzheimer's like neuropathological process in rat brain.

Amyloid-ß (Aß) accumulation in the brain is a pathological hallmark of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been implicated in aetiology of neurodegenerative disorders. We studied the involvement of ER stress in Aß-induced neuronal degeneration in rat brain to correlate it with cellular and molecular modifications in Aß-induced Alzheimer's like neuropathological process. Aß (1-42) (5 µg) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats. Acetylcholinesterase (AChE) activity and histological alterations were observed in different brain regions. ER stress-associated proteins- glucose regulated protein-78 (GRP78), eukaryotic translation initiation factor-2α (eIF2α) and growth arrest and DNA damage-inducible protein-153 (GADD153), neuronal marker- microtubule associated protein-2 (MAP-2) and microglial protein- ionized calcium binding adaptor molecule-1 (Iba-1) were measured by western blot. Reduced glutathione (GSH), nitrite level and levels of caspase-12 and caspase-3 were also measured. ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneally, ip) was used to assess the specific role of ER stress. Aß (1-42)-induced increase in AChE activity, GRP78 and GADD protein levels, dephosphorylation of eIF2-α and caspase-12 and caspase-3 levels and decrease in GSH and MAP-2 levels were attenuated by salubrinal. Increase in Iba-1 protein and nitrite levels after Aß (1-42) administration were partially attenuated by salubrinal. Aß (1-42)-induced histological alterations were correlated with findings of ER stress. Results of present study implicate ER stress as a potential molecular mechanism in Aß-induced Alzheimer's like neuropathology which could serve as surrogate biomarker for study of AD progression and efficacy of therapeutic interventions for AD management.

Correction to: Endoplasmic Reticulum Stress Plays a Key Role in Rotenone-Induced Apoptotic Death of Neurons.

The original version of this article unfortunately contained a mistake.

Bisphenol A triggers axonal injury and myelin degeneration with concomitant neurobehavioral toxicity in C57BL/6J male mice.

Bisphenol A (BPA) is a ubiquitously distributed endocrine disrupting chemical (EDC). BPA exposure in humans has been a matter of concern due to its increased application in the products of day to day use. BPA has been reported to cause toxicity in almost all the vital organ systems even at a very low dose levels. It crosses the blood brain barrier and causes neurotoxicity. We studied the effect of BPA on the cerebral cortex of C57BL/6J mice and examined whether BPA exposure alters the expression of axonal and myelin structural proteins. Male mice were dosed orally to 40 µg and 400 µg BPA/kg body weight for 60 days. BPA exposure resulted in memory loss, muscle coordination deficits and allodynia. BPA exposure also caused degeneration of immature and mature oligodendrocytes as evaluated by decreased mRNA levels of 2',3'-cyclic nucleotide 3' phosphodiesterase (CNPase), nestin, myelin basic protein (MBP) and myelin-associated glycoprotein-1 (MAG-1) genes revealing myelin related pathology. It was observed that subchronic BPA exposure caused neuroinflammation through deregulation of inflammatory cytokines mRNA and protein expression which further resulted into neurotoxicity through axonal as well as myelin degeneration in the brain. BPA also caused increased oxidative stress in the brain. Our study indicates long-term subchronic low dose exposure to BPA has the potential to cause axonal degeneration and demyelination in the oligodendrocytes and neurons which may have implications in neurological and neuropsychological disorders including multiple sclerosis (MS), neuromyelitis optica and others.

Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology.

The present study was conducted to correlate the cellular and molecular alterations in Alzheimer's pathology employing streptozotocin (STZ) induced experimental rat model. The STZ was administered in rat brain bilaterally by intracerebroventricular route using stereotaxic surgery followed by donepezil dosing. The Alzheimer's related pathological marker like acetylcholinesterase (AChE) activity, tau phosphorylation and amyloid aggregation were observed after STZ administration. STZ treatment showed decreased glucose and glucose transporters (GLUT) level along with augmented level of calcium in both cortical and hippocampal regions of rat brain. Increased calcium level may correlate with endoplasmic reticulum (ER) stress and significantly increased expression of ER stress markers like GRP78, GADD and caspase-12 were observed in STZ treated rat brain. Cellular communication was also affected by STZ administration as observed by increased expression connexin 43. With this view the activation of astrocytes and microglia was also assessed and observed by augmented GFAP and cd11b expression which were partially inhibited with donepezil treatment. The significantly increased level of degenerating neurons, caspase-3 and DNA fragmentation was also observed in rat brain regions which were not inhibited with donepezil treatment and validating the clinical observations. In conclusion, study indicated the STZ induced occurrence of Alzheimer's pathology. Further, STZ administration also caused depleted glucose level, inhibited mitochondrial activity, augmented calcium levels, ER stress, altered cellular communication and neuronal death which were partially attenuated with donepezil treatment.

Neurodegenerative signaling factors and mechanisms in Parkinson's pathology.

Parkinson's disease (PD) is a chronic and progressive degenerative disorder of central nervous system which is mainly characterized by selective loss of dopaminergic neurons in the nigrostrial pathway. Clinical symptoms of this devastating disease comprise motor impairments such as resting tremor, bradykinesia, postural instability and rigidity. Current medications only provide symptomatic relief but fail to halt the dopaminergic neuronal death. While the etiology of dopaminergic neuronal death is not fully understood, combination of various molecular mechanisms seems to play a critical role. Studies from experimental animal models have provided crucial insights into the molecular mechanisms in disease pathogenesis and recognized possible targets for therapeutic interventions. Recent findings implicate the involvement of abnormal protein accumulation and phosphorylation, mitochondrial dysfunction, oxidative damage and deregulated kinase signaling as key molecular mechanisms affecting the normal function as well survival of dopaminergic neurons. Here we discuss the relevant findings on the PD pathology related mechanisms and recognition of the cell survival mechanisms which could be used as targets for neuroprotective strategies in preventing this devastating disorder.

Endoplasmic Reticulum Stress Instigates the Rotenone Induced Oxidative Apoptotic Neuronal Death: a Study in Rat Brain.

The present study was conducted to evaluate the involvement of endoplasmic reticulum stress in rotenone-induced oxidative neuronal death in rat brain. Rotenone (6 µg/3 µl) was administered intranigrally, unilaterally (right side) in SD rat brain. Neuronal morphology, expression level of tyrosine hydroxylase (TH) and endoplasmic reticulum (ER) stress markers like glucose-regulated protein 78 (GRP78), growth arrest and DNA damage-inducible gene 153 (GADD153), eukaryotic translation initiation factor 2α (p-eIF2α/eIF2α) and cleaved caspase-12 were estimated in the rat brain. Levels of reactive oxygen species (ROS), reduced glutathione (GSH) and enzymatic activities of glutathione peroxidase (GPx) and glutathione reductase (GRd) were estimated to assess the rotenone induced oxidative stress. Apoptotic death of neurons was assessed by estimating the mRNA level of caspase-3. Rotenone administration caused altered neuronal morphology, decreased expression of TH, augmented ROS level, decreased level of GSH and decreased activities of GPx and GRd enzymes which were significantly attenuated with the pretreatment of ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneal). Significantly increased levels of GRP78, GADD, dephosphorylated eIF2α and cleaved caspase-12 was also observed after rotenone administration, which was inhibited with the pretreatment of salubrinal. Rotenone-induced increased mRNA level of caspase-3 was also attenuated by pretreatment of salubrinal. Findings suggested that salubrinal treatment significantly inhibited the rotenone-induced neurotoxicity implicating that ER stress initiates the rotenone-induced oxidative stress and neuronal death.