scholarly journals Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders

2021 ◽  
Vol 14 (10) ◽  
pp. 1025
Author(s):  
Claudia Sagheddu ◽  
Miriam Melis ◽  
Anna Lisa Muntoni ◽  
Marco Pistis
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Evidence ◽  
Peroxisome Proliferator ◽  
Brain Disorders ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Agonists ◽  
The Central Nervous System ◽  
Peroxisome Proliferator Activated Receptors ◽  
Neuropsychiatric Conditions

Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors modulating, among others, anti-inflammatory and neuroprotective genes in diverse tissues. Both endogenous and synthetic PPAR agonists are approved treatments for metabolic and systemic disorders, such as diabetes, fatty liver disease, and dyslipidemia(s), showing high tolerability and safety profiles. Considering that some PPAR-acting drugs permeate through the blood–brain barrier, the possibility to extend their scope from the periphery to central nervous system has gained interest in recent years. Here, we review preclinical and clinical evidence that PPARs possibly exert a neuroprotective role, thereby providing a rationale for repurposing PPAR-targeting drugs to counteract several diseases affecting the central nervous system.

scholarly journals Peroxisome Proliferator-Activated Receptors (PPARs) as Potential Inducers of Antineoplastic Effects in CNS Tumors

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-9 ◽  
Author(s):  
Lars Tatenhorst ◽  
Eric Hahnen ◽  
Michael T. Heneka
Keyword(s):  
Central Nervous System ◽  
Hormone Receptors ◽  
Tumor Therapy ◽  
Peroxisome Proliferator ◽  
Ppar Agonists ◽  
The Central Nervous System ◽  
Peroxisome Proliferator Activated Receptors ◽  
Underlying Mechanisms

The peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors which belong to the superfamily of nuclear hormone receptors. In recent years it turned out that natural as well as synthetic PPAR agonists exhibit profound antineoplastic as well as redifferentiation effects in tumors of the central nervous system (CNS). The molecular understanding of the underlying mechanisms is still emerging, with partially controverse findings reported by a number of studies dealing with the influence of PPARs on treatment of tumor cells in vitro. Remarkably, studies examining the effects of these drugs in vivo are just beginning to emerge. However, the agonists of PPARs, in particular the thiazolidinediones, seem to be promising candidates for new approaches in human CNS tumor therapy.

scholarly journals Peroxisome proliferator–activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity

2010 ◽  
Vol 207 (8) ◽  
pp. 1599-1608 ◽  
Author(s):  
Shannon E. Dunn ◽  
Roopa Bhat ◽  
Daniel S. Straus ◽  
Raymond A. Sobel ◽  
Robert Axtell ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Autoimmune Inflammation ◽  
Enhanced Expression ◽  
Synthetic Ligand ◽  
Ifn Γ ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator–activated receptors (PPARs; PPAR-α, PPAR-δ, and PPAR-γ) comprise a family of nuclear receptors that sense fatty acid levels and translate this information into altered gene transcription. Previously, it was reported that treatment of mice with a synthetic ligand activator of PPAR-δ, GW0742, ameliorates experimental autoimmune encephalomyelitis (EAE), indicating a possible role for this nuclear receptor in the control of central nervous system (CNS) autoimmune inflammation. We show that mice deficient in PPAR-δ (PPAR-δ−/−) develop a severe inflammatory response during EAE characterized by a striking accumulation of IFN-γ+IL-17A− and IFN-γ+IL-17A+ CD4+ cells in the spinal cord. The preferential expansion of these T helper subsets in the CNS of PPAR-δ−/− mice occurred as a result of a constellation of immune system aberrations that included higher CD4+ cell proliferation, cytokine production, and T-bet expression and enhanced expression of IL-12 family cytokines by myeloid cells. We also show that the effect of PPAR-δ in inhibiting the production of IFN-γ and IL-12 family cytokines is ligand dependent and is observed in both mouse and human immune cells. Collectively, these findings suggest that PPAR-δ serves as an important molecular brake for the control of autoimmune inflammation.

scholarly journals Covering the Role of PGC-1α in the Central Nervous System

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 111
Author(s):  
Zuzanna Kuczynska ◽  
Erkan Metin ◽  
Michal Liput ◽  
Leonora Buzanska
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuromuscular Junctions ◽  
Deep Understanding ◽  
Cell Types ◽  
Postnatal Life ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Central Nervous System

The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the central nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.

scholarly journals PPARα Modulation-Based Therapy in Central Nervous System Diseases

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1168
Author(s):  
Deokho Lee ◽  
Yohei Tomita ◽  
William Allen ◽  
Kazuo Tsubota ◽  
Kazuno Negishi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hormone Receptors ◽  
Inflammatory Responses ◽  
Peroxisome Proliferator ◽  
Therapeutic Approaches ◽  
Cns Diseases ◽  
The Central Nervous System ◽  
Peroxisome Proliferator Activated Receptors

The burden of neurodegenerative diseases in the central nervous system (CNS) is increasing globally. There are various risk factors for the development and progression of CNS diseases, such as inflammatory responses and metabolic derangements. Thus, curing CNS diseases requires the modulation of damaging signaling pathways through a multitude of mechanisms. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ), and they work as master sensors and modulators of cellular metabolism. In this regard, PPARs have recently been suggested as promising therapeutic targets for suppressing the development of CNS diseases and their progressions. While the therapeutic role of PPARγ modulation in CNS diseases has been well reviewed, the role of PPARα modulation in these diseases has not been comprehensively summarized. The current review focuses on the therapeutic roles of PPARα modulation in CNS diseases, including those affecting the brain, spinal cord, and eye, with recent advances. Our review will enable more comprehensive therapeutic approaches to modulate PPARα for the prevention of and protection from various CNS diseases.

Clinical evidence for dose tolerance of the central nervous system in hypofractionated radiotherapy

2018 ◽  
Vol 7 (4) ◽  
pp. 293-305 ◽  
Author(s):  
Jinyu Xue ◽  
Bahman Emami ◽  
Jimm Grimm ◽  
Gregory J. Kubicek ◽  
Sucha O. Asbell ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Clinical Evidence ◽  
Hypofractionated Radiotherapy ◽  
The Central Nervous System ◽  
Dose Tolerance

Neuropsychiatry of aggression

2020 ◽  
pp. 379-392
Author(s):  
Shoumitro (Shoumi) Deb ◽  
Tanya Deb
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Conduct Disorder ◽  
Personality Disorders ◽  
Assessment Methods ◽  
Mood Stabilizers ◽  
Psychological Issues ◽  
Intermittent Explosive Disorder ◽  
The Central Nervous System ◽  
Neuropsychiatric Conditions

Conditions affecting the central nervous system, such as trauma or degenerative illness, often lead to neurobehavioural disorders. One of the most difficult of these to treat is aggression. Outwardly directed aggression can be divided into two types—reactive and proactive—the first of which is less structured and generally presents with visible anger, while the latter is structured and premeditated. While there exists no specific diagnostic criteria for either type of aggression, the closest that exist are intermittent explosive disorder (IED) for the former and conduct disorder (CD), which has been known to evolve into personality disorders (PDs), for the latter. This chapter explores the relation between aggression and other neuropsychiatric conditions, beginning with its neurobiological underpinnings. It then describes assessment methods, such as the Behaviour itself, Medical/ organic issues, Person showing the behaviour, Psychiatric/psychological issues, and Social/ occupational/ personal issues (BMPPS) model, before discussing treatments, both pharmacological and non-pharmacological. For the former, the effectiveness of various medications is discussed, from antipsychotics to mood stabilizers.

scholarly journals Dexamethasone promotes IL-4-induced alternative activation at PPARγ point, instead of upstream STAT6 in BV2 microglial cells

2020 ◽  
Author(s):  
Zongfeng Chen ◽  
Liang Zhang ◽  
Xin Xue ◽  
Peng Liu ◽  
Xiang Yin ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Therapeutic Potential ◽  
Polarization State ◽  
Microglial Cells ◽  
Alternative Activation ◽  
Peroxisome Proliferator ◽  
Activation Markers ◽  
Arginase 1 ◽  
The Central Nervous System

Abstract Background Microglia are innate immune effector cells in the central nervous system and play an extremely important role in the physiological processes of the central nervous system. When microglia are activated, there are two polarization states, M1 and M2 phenotype. Dexamethasone is a glucocorticoid widely used in clinical practice, which pharmacological effects are mainly anti-inflammatory, anti-toxic. However, whether Dexamethasone affects polarization state of microglia is unknown. In this study, we investigate the effect of Dexamethasone on IL-4-induced alternative activation in murine BV-2 microglial cells. Methods BV-2 cells were incubated with Dexamethasone alone, IL-4 alone, or the combination of Dexamethasone and IL-4. Western blot and immunofluorescence were performed to detect protein levels of alternative activation markers arginase 1 (Arg1), found in inflammatory zone 1 (FIZZ1). Moreover, we investigated the effects of Dexamethasone on IL-4 induced activation of signal transducer and activators of transcription 6 (STAT6) and peroxisome proliferator-activated receptor-gamma (PPARγ). Results Dexamethasone promoted IL-4 induced microglia alternative activation by increasing the expression of Arg1 and FIZZ1. Dexamethasone also enhanced the expression of PPARγ. These effects were reversed by RU486 (a Dexamethasone antagonist). Further, the effects of Dexamethasone and IL-4 on Arg1 and FIZZ1 were blocked by the application of GW9662 (a PPARγ antagonist). Conclusions Our studies confirm that Dexamethasone promotes IL-4 induced alternative activation via STAT6/PPARγ signaling pathways in microglia. At the same time, it was confirmed that Dexamethasone acts on PPARγ instead of STAT6. These findings support that Dexamethasone has a therapeutic potential for neuroinflammatory diseases via alternative activation.

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