51 research outputs found
The Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines, reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics of this model and the contribution of neuroinflammatory processes, induced by the in vivo administration of bacterial endotoxin, to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD model in the development of an early-stage specific diagnostic biomarker is also emphasized
MicroRNAs and Multiple Sclerosis
MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease
The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson's Disease
Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases as strict regulation of integrated mitochondrial functions is essential for neuronal signaling, plasticity, and transmitter release. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD). Several PD-associated genes interface with mitochondrial dynamics regulating the structure and function of the mitochondrial network. Mitochondrial dysfunction can induce neuron death through a plethora of mechanisms. Both mitochondrial dysfunction and neuroinflammation, a common denominator of PD, lead to an increased production of reactive oxygen species, which are detrimental to neurons. The transcription factor nuclear factor E2-related factor 2 (Nrf2, NFE2L2) is an emerging target to counteract mitochondrial dysfunction and its consequences in PD. Nrf2 activates the antioxidant response element (ARE) pathway, including a battery of cytoprotective genes such as antioxidants and anti-inflammatory genes and several transcription factors involved in mitochondrial biogenesis. Here, the current knowledge about the role of mitochondrial dysfunction in PD, Nrf2/ARE stress-response mechanisms, and the evidence for specific links between this pathway and PD are summarized. The neuroprotection of nigral dopaminergic neurons by the activation of Nrf2 through several inducers in PD is also emphasized as a promising therapeutic approach
The Adverse Effects of Air Pollution on the Nervous System
Exposure to ambient air pollution is a serious and common public health concern associated with growing morbidity and mortality worldwide. In the last decades, the adverse effects of air pollution on the pulmonary and cardiovascular systems have been well established in a series of major epidemiological and observational studies. In the recent past, air pollution has also been associated with diseases of the central nervous system (CNS), including stroke, Alzheimer’s disease, Parkinson’s disease, and neurodevelopmental disorders. It has been demonstrated that various components of air pollution, such as nanosized particles, can easily translocate to the CNS where they can activate innate immune responses. Furthermore, systemic inflammation arising from the pulmonary or cardiovascular system can affect CNS health. Despite intense studies on the health effects of ambient air pollution, the underlying molecular mechanisms of susceptibility and disease remain largely elusive. However, emerging evidence suggests that air pollution-induced neuroinflammation, oxidative stress, microglial activation, cerebrovascular dysfunction, and alterations in the blood-brain barrier contribute to CNS pathology. A better understanding of the mediators and mechanisms will enable the development of new strategies to protect individuals at risk and to reduce detrimental effects of air pollution on the nervous system and mental health
Melatonin Attenuates LPS-Induced Acute Depressive-Like Behaviors and Microglial NLRP3 Inflammasome Activation Through the SIRT1/Nrf2 Pathway.
peer reviewedInflammation is a crucial component of various stress-induced responses that contributes to the pathogenesis of major depressive disorder (MDD). Depressive-like behavior (DLB) is characterized by decreased mobility and depressive behavior that occurs in systemic infection induced by Lipopolysaccharide (LPS) in experimental animals and is considered as a model of exacerbation of MDD. We assessed the effects of melatonin on behavioral changes and inflammatory cytokine expression in hippocampus of mice in LPS-induced DLB, as well as its effects on NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation, oxidative stress and pyroptotic cell death in murine microglia in vitro. Intraperitoneal 5 mg/kg dose of LPS was used to mimic depressive-like behaviors and melatonin was given at a dose of 500 mg/kg for 4 times with 6 h intervals, starting at 2 h before LPS administration. Behavioral assessment was carried out at 24 h post-LPS injection by tail suspension and forced swimming tests. Additionally, hippocampal cytokine and NLRP3 protein levels were estimated. Melatonin increased mobility time of LPS-induced DLB mice and suppressed NLRP3 expression and interleukin-1β (IL-1β) cleavage in the hippocampus. Immunofluorescence staining of hippocampal tissue showed that NLRP3 is mainly expressed in ionized calcium-binding adapter molecule 1 (Iba1) -positive microglia. Our results show that melatonin prevents LPS and Adenosine triphosphate (ATP) induced NLRP3 inflammasome activation in murine microglia in vitro, evidenced by inhibition of NLRP3 expression, Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation, caspase-1 cleavage and interleukin-1β (IL-1β) maturation and secretion. Additionally, melatonin inhibits pyroptosis, production of mitochondrial and cytosolic reactive oxygen species (ROS) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. The beneficial effects of melatonin on NLRP3 inflammasome activation were associated with nuclear factor erythroid 2-related factor 2 (Nrf2) and Silent information regulator 2 homolog 1 (SIRT1) activation, which were reversed by Nrf2 siRNA and SIRT1 inhibitor treatment
Erythropoietin and Parkinson's disease: Suggested mechanisms, and therapeutic implications
The involvement of Nrf2-mediated antioxidant defense in neurovascular protection by activated protein C
The natural anticoagulant protein, activated protein C, is neuroprotective and vascular protective, however, the precise mechanisms of its beneficial effect against neurovascular injury are not entirely known. Activated protein C may modulate antioxidant defense system at the transcriptional level. © 2009 Elsevier Ltd. All rights reserved
- …