Pharmacological Blockade of PPARα Exacerbates Inflammatory Pain-Related Impairment of Spatial Memory in Rats

Gaspar, Jessica C.; Healy, Catherine; Ferdousi, Mehnaz; Roche, Michelle; Finn, David P.

doi:10.3390/biomedicines9060610

Cited by 8 publications

(11 citation statements)

References 103 publications

(135 reference statements)

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“…The same remarks suggesting an effect of PEA in rescuing memory deficits and injured hippocampal neurons, possibly by exerting anti-inflammatory and neuroprotective effects, were reported in preclinical models of VaD ( 36 , 42 ). Finally, converging evidence for an improving effect of PEA administration on learning and memory and their biological underpinnings was also found in the context of brain ischemia reperfusion injury ( 24 ), PD ( 39 ), SNI ( 40 , 41 , 49 ), TBI ( 28 ), CFA ( 51 ), and high-fat diet ( 48 ), where cognitive decline is a common complication of the disease.…”

Section: Resultsmentioning

confidence: 94%

“…Most evidence regarding a potential therapeutic effect of PEA in NCDs was gathered from preclinical studies administering the compound to animal models of NCDs ( Table 1B ), including AD ( 20 , 31 , 38 , 46 , 47 , 50 ), Aβ-exposed ( 34 ), middle cerebral artery occlusion (MCAo) ( 24 ), PD ( 39 ), vascular dementia (VaD) ( 36 , 42 ), spared nerve injury (SNI) ( 40 , 41 , 49 ), TBI ( 28 ), Complete Freund's Adjuvant (CFA) ( 51 ), and high-fat diet ( 48 ) models. Despite the evidence of similar methodologies across the reviewed studies, a certain heterogeneity was found in terms of animal type [mice ( 20 , 28 , 31 , 36 , 38 – 42 , 46 , 48 – 50 ), rat ( 24 , 34 , 47 , 51 )], period of exposure [from 4 to 5 weeks old to 21 months old), PEA formulation [alone unspecified, PEA ( 31 , 34 , 50 , 51 ); alone micronized, PEAm ( 39 ); alone ultra-micronized, um-PEA ( 20 , 38 , 40 , 41 , 46 , 48 ); combined with oxazoline, PEA-OXA ( 42 , 49 ); combined with luteolin, PEALut ( 24 , 28 , 36 , 47 )], PEA mode of administration [intraperitoneal ( 34 , 40 , 41 , 47 , 49 , 51 ), subcutaneous ( 20 , 31 , 38 ), oral ( 24 ,…”

Section: Resultsmentioning

confidence: 99%

“…Seven studies analyzed PEA levels in the brain and tissues of animal models of NCDs ( Tables 1B , 2B ), including VaD ( 36 , 42 ), SNI ( 41 ), CFA ( 51 ) and genic models of AD ( 43 , 46 ) and related conditions ( 44 ). Genetically inducing a reduction in PEA levels resulted in changes in hippocampal synaptic activity and aberrant cognition ( 44 ).…”

Section: Resultsmentioning

confidence: 99%

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Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence

et al. 2022

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Cognitive decline is believed to be associated with neurodegenerative processes involving excitotoxicity, oxidative damage, inflammation, and microvascular and blood-brain barrier dysfunction. Interestingly, research evidence suggests upregulated synthesis of lipid signaling molecules as an endogenous attempt to contrast such neurodegeneration-related pathophysiological mechanisms, restore homeostatic balance, and prevent further damage. Among these naturally occurring molecules, palmitoylethanolamide (PEA) has been independently associated with neuroprotective and anti-inflammatory properties, raising interest into the possibility that its supplementation might represent a novel therapeutic approach in supporting the body-own regulation of many pathophysiological processes potentially contributing to neurocognitive disorders. Here, we systematically reviewed all human and animal studies examining PEA and its biobehavioral correlates in neurocognitive disorders, finding 33 eligible outputs. Studies conducted in animal models of neurodegeneration indicate that PEA improves neurobehavioral functions, including memory and learning, by reducing oxidative stress and pro-inflammatory and astrocyte marker expression as well as rebalancing glutamatergic transmission. PEA was found to promote neurogenesis, especially in the hippocampus, neuronal viability and survival, and microtubule-associated protein 2 and brain-derived neurotrophic factor expression, while inhibiting mast cell infiltration/degranulation and astrocyte activation. It also demonstrated to mitigate β-amyloid-induced astrogliosis, by modulating lipid peroxidation, protein nytrosylation, inducible nitric oxide synthase induction, reactive oxygen species production, caspase3 activation, amyloidogenesis, and tau protein hyperphosphorylation. Such effects were related to PEA ability to indirectly activate cannabinoid receptors and modulate proliferator-activated receptor-α (PPAR-α) activity. Importantly, preclinical evidence suggests that PEA may act as a disease-modifying-drug in the early stage of a neurocognitive disorder, while its protective effect in the frank disorder may be less relevant. Limited human research suggests that PEA supplementation reduces fatigue and cognitive impairment, the latter being also meta-analytically confirmed in 3 eligible studies. PEA improved global executive function, working memory, language deficits, daily living activities, possibly by modulating cortical oscillatory activity and GABAergic transmission. There is currently no established cure for neurocognitive disorders but only treatments to temporarily reduce symptom severity. In the search for compounds able to protect against the pathophysiological mechanisms leading to neurocognitive disorders, PEA may represent a valid therapeutic option to prevent neurodegeneration and support endogenous repair processes against disease progression.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence

et al. 2022

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“…Recent studies have pointed to a possible role of PPARs in anxiety and cognition. Our recent work has shown that the administration of a PPARα antagonist exacerbated inflammatory pain-related impairment of spatial memory in rats [ 57 ]. Youssef et al (2019) showed that the administration of a PPARγ antagonist blocked the anxiolytic effect of beta-caryophyllene.…”

Section: Discussionmentioning

confidence: 99%

Effects of Intra-BLA Administration of PPAR Antagonists on Formalin-Evoked Nociceptive Behaviour, Fear-Conditioned Analgesia, and Conditioned Fear in the Presence or Absence of Nociceptive Tone in Rats

et al. 2022

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There is evidence for the involvement of peroxisome proliferator-activated receptors (PPARs) in pain, cognition, and anxiety. However, their role in pain–fear interactions is unknown. The amygdala plays a key role in pain, conditioned fear, and fear-conditioned analgesia (FCA). We investigated the effects of intra-basolateral amygdala (BLA) administration of PPARα, PPARβ/δ, and PPARγ antagonists on nociceptive behaviour, FCA, and conditioned fear in the presence or absence of nociceptive tone. Male Sprague-Dawley (SD) rats received footshock (FC) or no footshock (NFC) in a conditioning arena. Twenty-three and a half hours later, rats received an intraplantar injection of formalin or saline and, 15 min later, intra-BLA microinjections of vehicle, PPARα (GW6471) PPARβ/δ (GSK0660), or PPARγ (GW9662) antagonists before arena re-exposure. Pain and fear-related behaviour were assessed, and neurotransmitters/endocannabinoids measured post-mortem. Intra-BLA administration of PPARα or PPARγ antagonists potentiated freezing in the presence of nociceptive tone. Blockade of all PPAR subtypes in the BLA increased freezing and BLA dopamine levels in NFC rats in the absence of nociceptive tone. Administration of intra-BLA PPARα and PPARγ antagonists increased levels of dopamine in the BLA compared with the vehicle-treated counterparts. In conclusion, PPARα and PPARγ in the BLA play a role in the expression or extinction of conditioned fear in the presence or absence of nociceptive tone.

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“…They are present at key peripheral, spinal, and supraspinal sites involved in pain processing [ 27 ], and the increase in PPARs activation or protein expression in the spinal cord has been demonstrated in several animal models of chronic pain [ 28 ]. Indeed, several studies suggested that their pharmacological manipulation could represent a promising therapeutic strategy in the control of different types of neuropathic pain [ 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

Rullo

Franchi

Amodeo

et al. 2021

IJMS

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Chemotherapy-induced neuropathy (CIN) is a major adverse effect associated with many chemotherapeutics, including bortezomib (BTZ). Several mechanisms are involved in CIN, and recently a role has been proposed for prokineticins (PKs), a chemokine family that induces proinflammatory/pro-algogen mediator release and drives the epigenetic control of genes involved in cellular differentiation. The present study evaluated the relationships between epigenetic mechanisms and PKs in a mice model of BTZ-induced painful neuropathy. To this end, spinal cord alterations of histone demethylase KDM6A, nuclear receptors PPARα/PPARγ, PK2, and pro-inflammatory cytokines IL-6 and IL-1β were assessed in neuropathic mice treated with the PK receptors (PKRs) antagonist PC1. BTZ treatment promoted a precocious upregulation of KDM6A, PPARs, and IL-6, and a delayed increase of PK2 and IL-1β. PC1 counteracted allodynia and prevented the increase of PK2 and of IL-1β in BTZ neuropathic mice. The blockade of PKRs signaling also opposed to KDM6A increase and induced an upregulation of PPAR gene transcription. These data showed the involvement of epigenetic modulatory enzymes in spinal tissue phenomena associated with BTZ painful neuropathy and underline a role of PKs in sustaining the increase of proinflammatory cytokines and in exerting an inhibitory control on the expression of PPARs through the regulation of KDM6A gene expression in the spinal cord.

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Pharmacological Blockade of PPARα Exacerbates Inflammatory Pain-Related Impairment of Spatial Memory in Rats

Cited by 8 publications

References 103 publications

Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence

Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence

Effects of Intra-BLA Administration of PPAR Antagonists on Formalin-Evoked Nociceptive Behaviour, Fear-Conditioned Analgesia, and Conditioned Fear in the Presence or Absence of Nociceptive Tone in Rats

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

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