Mitochondrial Dysfunction and Parkinson's Disease: Pathogenesis and Therapeutic Strategies.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder whose pathogenesis is not completely understood. Mitochondrial dysfunction and increased oxidative stress have been considered as major causes and central events responsible for the progressive degeneration of dopaminergic (DA) neurons in PD. Therefore, investigating mitochondrial disorders plays a role in understanding the pathogenesis of PD and can be an important therapeutic target for this disease. This study discusses the effect of environmental, genetic and biological factors on mitochondrial dysfunction and also focuses on the mitochondrial molecular mechanisms underlying neurodegeneration, and its possible therapeutic targets in PD, including reactive oxygen species generation, calcium overload, inflammasome activation, apoptosis, mitophagy, mitochondrial biogenesis, and mitochondrial dynamics. Other potential therapeutic strategies such as mitochondrial transfer/transplantation, targeting microRNAs, using stem cells, photobiomodulation, diet, and exercise were also discussed in this review, which may provide valuable insights into clinical aspects. A better understanding of the roles of mitochondria in the pathophysiology of PD may provide a rationale for designing novel therapeutic interventions in our fight against PD.

Anti-inflammatory, anti-apoptotic, and neuroprotective potentials of anethole in Parkinson's disease-like motor and non-motor symptoms induced by rotenone in rats.

Parkinson's disease (PD) is a complex neurological disorder characterized by a combination of motor and non-motor symptoms (NMS). Antioxidant and anti-inflammatory compounds are considered a potential therapeutic strategy against PD. The present study examined the neuroprotective effects of anethole as a potent antioxidant and anti-inflammatory agent against motor and non-motor deficits induced by rotenone toxicity. Rats were treated with anethole (62.5, 125, and 250 mg/kg, i.g) concomitantly with rotenone (2 mg/kg, s.c) for 5 weeks. After the treatment, behavioral tests were performed to evaluate motor function and depression-/anxiety-like behaviors. After the behavioral tests, rats were decapitated and brains were removed for histological analysis. Striatum samples were also isolated for neurochemical, and molecular analysis. Our data showed that rotenone-induced motor deficit, anxiety-and depression-like behaviors were significantly improved in rats treated with anethole. Furthermore, anethole treatment reduced inflammatory cytokines tumor necrosis factor α (TNFα) and Interleukin 6 (IL-6), and increased anti-inflammatory cytokine IL-4 in the striatum of rotenone-induced PD rats. Western blot analysis showed that treatment with anethole markedly suppressed caspase-3 activation induced by rotenone. Moreover, histological examination of striatum showed an increase in the number of surviving neurons after treatment with anethole. Anethole also significantly enhanced the striatal levels of dopamine in rotenone-induced PD rats. In addition, treatment with L-Dopa as a positive control group had effects similar to those of anethole on histological, neurochemical, and molecular parameters in rotenone-induced parkinsonian rats. Our results suggested the neuroprotective effects of anethole through anti-inflammatory, anti-apoptotic, and antioxidant mechanisms against rotenone-induced toxicity in rats.

Anethole attenuates motor dysfunctions, striatal neuronal activity deficiency and blood brain barrier permeability by decreasing striatal α-synuclein and oxidative stress in rotenone-induced Parkinson's disease of male rats.

INTRODUCTION: Anethole is the main compound of the essential oil of anise and several other plants, which has antioxidant, anti-inflammatory, and neuroprotective properties. Oxidative stress is considered as an important factor in the pathogenesis of PD. In the present study, we aimed to investigate the effects of anethole against rotenone-induced PD. METHODS: Male Wistar rats were randomly divided into six groups. Control group received DMSO + sunflower oil, model group received rotenone (2 mg/kg, s.c, daily for 35 days), positive control group received L-Dopa, and test groups received anethole (62.5, 125, and 250 mg/kg, i.g, daily for 35 days) 1 hour before each rotenone injection. Body weight changes, rotarod test, stride length test, and extracellular single unit recording were performed after treatment. After behavioral test, Brain water content and blood brain barrier (BBB) permeability were evaluated, and the levels of malondialdehyde (MDA), superoxide dismutases (SOD), alpha-synuclein and MAO-B were measured in the striatum. RESULTS: Chronic administration of rotenone induced body weight loss and caused significant dysfunction in locomotor activity, neuronl firing rate, and BBB. Rotenone also decreased SOD activity, increased MDA level, and elevated the expression of alpha-synuclein and MAO-B in the striatum. However, treatment with anethole attenuated body weight loss, motor function, neuronal activity, and BBB function. Furthermore, Anethole treatment attenuated oxidative stress and decreased the expression of alpha-synuclein and MAO-B compared to the rotenone group. CONCLUSION: Our results show that through its antioxidant properties, aethole can improve the cellular, molecular and behavioral characteristics of rotenone-induced Parkinson's disease.

Resveratrol as an antitumor agent for glioblastoma multiforme: Targeting resistance and promoting apoptotic cell deaths.

Glioblastoma multiforme (GBM) is one of the most aggressive brain and spinal cord tumors. Despite the significant development in application of antitumor drugs, no significant increases have been observed in the survival rates of patients with GBM, as GBM cells acquire resistance to conventional anticancer therapeutic agents. Multiple studies have revealed that PI3K/Akt, MAPK, Nanog, STAT 3, and Wnt signaling pathways are involved in GBM progression and invasion. Besides, biological processes such as anti-apoptosis, autophagy, angiogenesis, and stemness promote GBM malignancy. Resveratrol (RESV) is a non-flavonoid polyphenol with high antitumor activity, the potential of which, regulating signaling pathways involved in cancer malignancy, have been demonstrated by many studies. Herein, we present the potential of RESV in both single and combination therapy- targeting various signaling pathways- which induce apoptotic cell death, re-sensitize cancer cells to radiotherapy, and induce chemo-sensitizing effects to eventually inhibit GBM progression.

MiR-33-5p Regulates CREB to Induce Morphine State-dependent Memory in Rats: Interaction with the µ Opioid Receptor.

The aim of the present study was to examine the hypothesis that miR-33-5p attenuates morphine state-dependent (StD) memory via the µ opioid receptor by regulating cyclic AMP response element-binding protein (CREB). The effects of post-training morphine and morphine StD memory and their interaction with pre-test naloxone were evaluated using a single-trial inhibitory avoidance paradigm. Then, the hippocampal miR-33-5p gene and pCREB/CREB protein expression profiles were evaluated using quantitative real-time PCR and western blotting, respectively. We found that while post-training morphine and morphine StD memory respectively up- and down-regulate the miR-33-5p expression profile in the hippocampus, the reverse results are true for the expression of pCREB/CREB. Pre-test naloxone antagonized the response. Overall, our findings suggest that the expression levels of miR-33-5p in the hippocampus set the basis for morphine StD memory with low miR-33-5p enabling state dependency. The mechanism is mediated via miR33-5p and CREB signaling with the interaction of the µ opioid receptor. This finding may be used as a potential strategy for ameliorating morphine-induced memory-related disorders.

Curcumin mitigates lipopolysaccharide-induced anxiety/depression-like behaviors, blood-brain barrier dysfunction and brain edema by decreasing cerebral oxidative stress in male rats.

Oxidative stress is a well-known risk factor for the development of anxiety and depression disorders. Curcumin, a natural compound, is an antioxidant with well-known neuroprotective functions. In the present study, we aimed to investigate the putative anxiolytic and antidepressant-like properties of curcumin, and its protective effects on blood-brain barrier (BBB) dysfunction and brain edema in lipopolysaccharide (LPS)-challenged rats, and the potential involvement of antioxidant properties of curcumin pretreatment. For this purpose, rats received 50 mg/kg of curcumin (gavage, 14 consecutive days) or saline prior to intraperitoneal administration of LPS. Subsequently, animals were submitted to the elevated plus maze (EPM), open field tests (OFT), and forced swimming test (FST), 24 h after LPS administration. Furthermore, BBB permeability and brain water contents were assessed in the brain tissue. Hence, GPX and SOD enzyme activity and MDA concentration were determined in the brain tissue using ELISA assay. Our results showed that curcumin significantly reduced LPS-induced anxiety-like behavior in EPM and OFT, increased exploratory activity, but without significant change in the locomotor activity. Pretreatment with curcumin attenuate LPS-induced BBB permeability and brain water content. Our biochemical assays showed that curcumin significantly increased the activity of SOD and GPX enzymes, as well as reduced MDA concentration in the brain tissue after LPS administration. Together, these results suggest that pretreatment with curcumin might mitigate LPS- induced anxiety and depressive-like behaviors, and attenuate brain edema and BBB permeability, possibly by its antioxidant properties.