Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis

Pinna, Graziano

doi:10.3389/fnins.2018.00482

Cited by 22 publications

(13 citation statements)

References 93 publications

(156 reference statements)

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“…A PPAR-α-allopregnanolone (i.e., endocannabinoid-like/ neurosteroids) cross-talk may have an impact for establishing relevant novel targets for the treatment of PTSD and major depression [9]. Intriguingly, these newly observed link between the endocannabinoid-like system and biosynthesis of neurosteroids may additionally provide bio-signatures for the diagnosis and treatment of psychiatric disorders, which still rely on subjective measures based on the DSM-5 criteria [120]. Furthermore, PPAR-γ agonists, including pioglitazone, have shown promising antidepressant effects in several clinical trials [16,[65][66][67].…”

Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer’s disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes.

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Section: Neurodevelopmental Disordersmentioning

confidence: 99%

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Tufano

Pinna

2020

Molecules

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“…Likewise, in humans with major depression (PTSD not assessed), fluoxetine and fluvoxamine increased CSF allo + pregnan levels in association with decreases in depressive symptoms (Uzunova et al, 1998). Other compounds that induce neurosteroidogenesis [e.g., 18kDa translocator protein (TSPO) ligands (Rupprecht et al, 2010) or agonists at the cannabinoid type 1 (CB1) receptor or peroxisome pro-liferatoractivated receptor alpha (PPAR-α (Pinna, 2018)] also may be therapeutic in PTSD, but perhaps only if downstream blocks in Allopregnanolone and/or pregnanolone synthesis don't interfere. example, in healthy individuals, acutely administered pregnenolone compared to placebo, as well as the serum ratio of Allopregnanolone pregnenolone, were associated with increased dmPFC to amygdala connectivity, which in turn was associated with better emotion regulation (Sripada et al, 2013).…”

Section: Implications For Treatmentmentioning

confidence: 99%

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD

Rasmusson

King

Valovski

et al. 2019

Psychoneuroendocrinology

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Allopregnanolone and pregnanolone (together termed allo + pregnan) are neurosteroid metabolites of proges-terone that equipotently facilitate the action of gamma-amino-butyric acid (GABA) at GABA A receptors. The adrenal steroid dehydroepiandrosterone (DHEA) allosterically antagonizes GABA A receptors and facilitates N-methyl-D-aspartate (NMDA) receptor function. In prior research, premenopausal women with posttraumatic stress disorder (PTSD) displayed low cerebrospinal fluid (CSF) levels of allo + pregnan [undifferentiated by the gas chromatographymass spectrometry (GC-MS) method used] that correlated strongly and negatively with PTSD reexperiencing and negative mood symptoms. A PTSD-related decrease in the ratio of allo + pregnan to 5α-dihydroprogesterone (5α-DHP: immediate precursor for Allopregnanolone) suggested a block in synthesis of these neurosteroids at 3α-hydroxysteroid dehydrogenase (3α-HSD). In the current study, CSF was collected from unmedicated, tobacco-free men with PTSD (n = 13) and trauma-exposed healthy controls (n = 17) after an overnight fast. Individual CSF steroids were quantified separately by GC-MS. In the men with PTSD, allo + pregnan correlated negatively with Clinician-Administered PTSD Scale (CAPS-IV) total (ρ = −0.74, p = 0.006)and CAPS-IV derived Simms dysphoria cluster (ρ = −0.71, p = 0.01) scores. The allo + pregnan to DHEA ratio

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“…Of interest to trauma- and stressor-related psychiatric disorders, PEA induces potent antidepressant-like behavioral responses (Yu et al 2011) and, through induction of cannabinoid 2 receptors, alters the phenotype of macrophages and microglia (Guida et al 2017). Recent studies have demonstrated PEA increases the biosynthesis of allopregnanolone, an endocannabinoid, in the spinal cord, brainstem, hippocampus, and amygdala, effects that are associated with faster fear extinction learning and improvement of aggression in socially isolated mice (Sasso et al 2012; Locci and Pinna 2017; Pinna 2018). Future studies should determine if 10( Z )-hexadecenoic acid is sufficient to induce the enhanced fear extinction learning previously demonstrated using whole, heat-killed M. vaccae (Fox et al 2017), and to what extent these effects are mediated by PPARα.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties

et al. 2019

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Rationale Mycobacterium vaccae (NCTC 11659) is an environmental saprophytic bacterium with anti-inflammatory, immunoregulatory, and stress resilience properties. Previous studies have shown that whole, heat-killed preparations of M. vaccae prevent allergic airway inflammation in a murine model of allergic asthma. Recent studies also demonstrate that immunization with M. vaccae prevents stress-induced exaggeration of proinflammatory cytokine secretion from mesenteric lymph node cells stimulated ex vivo, prevents stress-induced exaggeration of chemically induced colitis in a model of inflammatory bowel disease, and prevents stress-induced anxiety-like defensive behavioral responses. Furthermore, immunization with M. vaccae induces anti-inflammatory responses in the brain and prevents stress-induced exaggeration of microglial priming. However, the molecular mechanisms underlying anti-inflammatory effects of M. vaccae are not known. Objectives Our objective was to identify and characterize novel anti-inflammatory molecules from M. vaccae NCTC 11659. Methods We have purified and identified a unique anti-inflammatory triglyceride, 1,2,3-tri [Z-10-hexadecenoyl] glycerol, from M. vaccae and evaluated its effects in freshly isolated murine peritoneal macrophages. Results The free fatty acid form of 1,2,3-tri [Z-10-hexadecenoyl] glycerol, 10(Z)-hexadecenoic acid, decreased lipopolysaccharide-stimulated secretion of the proinflammatory cytokine IL-6 ex vivo. Meanwhile, next-generation RNA sequencing revealed that pretreatment with 10(Z)-hexadecenoic acid upregulated genes associated with peroxisome proliferator-activated receptor alpha (PPARα) signaling in lipopolysaccharide-stimulated macrophages, in association with a broad transcriptional repression of inflammatory markers. We confirmed using luciferase-based transfection assays that 10(Z)-hexadecenoic acid activated PPARα signaling, but not PPARγ, PPARδ, or retinoic acid receptor (RAR) α signaling. The effects of 10(Z)-hexadecenoic acid on lipopolysaccharide-stimulated secretion of IL-6 were prevented by PPARα antagonists and absent in PPARα-deficient mice. Conclusion Future studies should evaluate the effects of 10(Z)-hexadecenoic acid on stress-induced exaggeration of peripheral inflammatory signaling, central neuroinflammatory signaling, and anxiety- and fear-related defensive behavioral responses.

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Biomarkers for PTSD at the Interface of the Endocannabinoid and Neurosteroid Axis

Cited by 22 publications

References 93 publications

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Is There a Future for PPARs in the Treatment of Neuropsychiatric Disorders?

Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD

Identification and characterization of a novel anti-inflammatory lipid isolated from Mycobacterium vaccae, a soil-derived bacterium with immunoregulatory and stress resilience properties

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