Role of PPAR<i>γ</i>in the Differentiation and Function of Neurons

Quintanilla, Rodrigo A.; Utreras, Elías; Cabezas-Opazo, Fabian

doi:10.1155/2014/768594

Cited by 60 publications

(37 citation statements)

References 76 publications

(183 reference statements)

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“…CBD can bind to PPARγ, and PPARγ activation is becoming an important target in neurodegeneration, as it is antiinflammatory and its activation improves mitochondrial function and resistance to oxidative stress [54,140]. Here, the protective effects of CBD in an Aβ-induced neuroinflammatory mouse model were abolished by a PPARγ antagonist, but no evidence was given as to whether this was a direct or indirect effect [198].…”

Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 95%

“…Related to VDAC1 as a mitochondrial target is the effect of CBD via PPARγ, a nuclear receptor type expressed in brain with a significant role in regulating metabolism, immune response, and development. However, while such a physiological role could have profound implications for epilepsy, no specific link between PPARγ and epilepsy has yet been made, and direct effects of CBD at (c.f., via) this target have yet to be demonstrated [140].…”

Section: Cbd Ion Channel Targets In Epilepsymentioning

confidence: 99%

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Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

448

323

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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excludin...

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Section: Cbd Receptor Targets In Neurodegenerationmentioning

confidence: 95%

Section: Cbd Ion Channel Targets In Epilepsymentioning

confidence: 99%

Molecular Targets of Cannabidiol in Neurological Disorders

Bih

Chen

Nunn³

et al. 2015

Neurotherapeutics

448

323

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“…PPAR roles include metabolic regulation in response to environmental cues, proliferation control, and cardiovascular homoeostasis; they modulate oxidative stress, inflammation, or insulin resistance. PPARs can antagonize neurodegeneration in AD/PD/cerebral ischaemia/brain trauma [139,161]. They may also be of therapeutic interest in the metabolic syndrome [58].…”

Section: Transcriptional and Post-transcriptional Regulators As Sirtumentioning

confidence: 99%

“…They may also be of therapeutic interest in the metabolic syndrome [58]. PPARs also modulate inflammation that partially mediates these pathologies [58,139,161,165]. PPARs may also constitute plausible targets in diabetes and diabetes-linked neuropathy.…”

Section: Transcriptional and Post-transcriptional Regulators As Sirtumentioning

confidence: 99%

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

Jęśko¹,

Strosznajder²

2016

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A b s t r a c tSirtuins vast number of targets in many cellular compartments, and some display additional enzymatic activities including mono(ADP-ribosyl)ation. SIRTs interact with multiple signalling proteins, transcription factors and enzymes including p53, FOXOs (forkhead box subgroup O), PPARs (peroxisome proliferator-activated receptors), NF-κB, and DNA-PK (DNA-dependent protein kinase). Sirtuins also interact extensively with the family of poly(ADPribose) polymerases (PARPs), a crucial and widespread class of NAD

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“…Interestingly, patients receiving such drugs were also protected from neurodegenerative pathologies. Indeed, PPARγ agonists promote neuronal development, protect cells from toxicity against various stresses and even protect neurons from Aβ toxicity and the accumulation of NFTs ultimately protecting the host from cognitive degeneration (rev in [197]). The PPARγ agonist LSN862 were also shown to be protective against dopaminergic degeneration and inflammatory markers in the MPTP-model of PD [198].…”

Section: Peroxisome Proliferator-activated Receptorsmentioning

confidence: 99%

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

Lomis¹

2015

J Diabetes Metab

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The gut microflora is a community of trillions of bacterial cells synergistically inhabiting the human gastrointestinal tract. These microbes contact everything that is consumed and release regulatory factors that affect host energy homeostasis, lipid and carbohydrate metabolism, activation of immune cells, oxidative state, epithelial cell wall integrity and even neurological signals. The gut microflora is essentially an independent organ supporting human health where imbalances in the gut community populations (dysbiosis) manifest in disease. Diabetes and neurodegenerative disorders such as Alzheimer's and Parkinson's disease share a similar molecular pathology rooted in gut microflora activity. Both of these conditions are associated with a dysbiosis characterized by low species diversity, a higher proportion of pathobionts at the expense of symbionts, an abundance of proinflammatory microbes and fewer butyrate-producing strains. Many of these factors can be ameliorated with Lactobacillus spp. and Bifidobacterium spp. probiotic treatment aimed to reestablish healthy gut microflora diversity. Indeed, certain commensal and pathogenic strains promote chronic low-grade inflammation that stresses cellular infrastructure eventually leading to apoptosis in both the pancreas and the brain. Also, lack of some beneficial fermentation products such as butyrate and ferulic acid initiates a cascade of events disrupting metabolic homeostasis. Finally, signaling initiated by the microflora and its metabolites has been shown to disrupt the delicate intracellular balance of PI3K/Akt/mTOR signaling, which fundamentally regulates events leading up to diabetes and neurodegenerative disease pathogenesis. The following review investigates the relationship between the manifestation and molecular signaling of diabetes and neurodegenerative disorders and how the balance of gut microflora populations is critical to both prevent and possibly treat these diseases.

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Role of PPARγin the Differentiation and Function of Neurons

Cited by 60 publications

References 76 publications

Molecular Targets of Cannabidiol in Neurological Disorders

Molecular Targets of Cannabidiol in Neurological Disorders

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

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