Role of PPARs in Progression of Anxiety: Literature Analysis and Signaling Pathways Reconstruction

Abstract

Peroxisome proliferator-activated receptor (PPAR) group includes three isoforms encoded by PPARG, PPARA, and PPARD genes. High concentrations of PPARs are found in parts of the brain linked to anxiety development, including hippocampus and amygdala. Among three PPAR isoforms, PPARG demonstrates the highest expression in CNS, where it can be found in neurons, astrocytes, and glial cells. Herein, the highest PPARG expression occurs in amygdala. However, little is known considering possible connections between PPARs and anxiety behavior. We reviewed possible connections between PPARs and anxiety. We used the Pathway Studio software (Elsevier). Signal pathways were created according to previously developed algorithms. SNEA was performed in Pathway Studio. Current study revealed 14 PPAR-regulated proteins linked to anxiety. Possible mechanism of PPAR involvement in neuroinflammation protection is proposed. Signal pathway reconstruction and reviewing aimed to reveal possible connection between PPARG and CCK-ergic system was conducted. Said analysis revealed that PPARG-dependent regulation of MME and ACE peptidase expression may affect levels of nonhydrolysed, i.e., active CCK-4. Impairments in PPARG regulation and following MME and ACE peptidase expression impairments in amygdala may be the possible mechanism leading to pathological anxiety development, with brain CCK-4 accumulation being a key link. Literature data analysis and signal pathway reconstruction and reviewing revealed two possible mechanisms of peroxisome proliferator-activated receptors involvement in pathological anxiety: (1) cytokine expression and neuroinflammation mechanism and (2) regulation of peptidases targeted to anxiety-associated neuropeptides, primarily CCK-4, mechanism.

The Efficacy and Mechanism of Kaempferol in Preventing perioperative neurocognitive disorders in the Elderly: Based on Network Pharmacology and Experimental Verification

“…Thus, inhibiting the activation of the JNK/p-JUN signaling pathway may have a positive impact on neuroprotection and cognitive function improvement. Peroxisome proliferator-activated receptor gamma (PPARG) is a nuclear receptor, proven to play a key role in regulating in ammatory responses and oxidative stress responses (Rudko et al 2020). PPARG signaling can enhance neuroplasticity and neural repair by affecting BDNF(Gold 2021).Kae , acts upon Peroxisome Proliferator-Activated Receptor Gamma (PPARG), curbing the generation of in ammatory mediators through an upregulation of PPARG expression, thus positively contributing to neuroprotection.…”

Time-course analysis of frontal gene expression profiles in the rat model of posttraumatic stress disorder and a comparison with the conditioned fear model

“…Other pathways such as PPAR signaling, VDR/RXR signaling, and corticotropin-releasing hormone signaling pathway were more significant in the early stage after SPS&FS exposure. PPAR signaling was indicated as actively regulating genes associated with lipid and carbohydrate metabolism ( Thibaut, 2017 ), and two other mechanisms were observed to contribute to anxiety formation: (1) neuroinflammation and gene expression of cytokine and (2) the hydrolysis of neuropeptide CCK-4 ( Domi et al, 2016 ; Rudko et al, 2020 ). Recent studies have suggested PPAR-α, which engages in neurosteroid biosynthesis, is especially critical for the regulation of emotion in PTSD and depression ( Locci and Pinna, 2019 ; Nisbett and Pinna, 2018 ).…”

Mechanism Underlying the Anxiolytic Effect of Cinnamomum Camphora Chvar. Borneol Essential Oil Revealed by Network Pharmacology

“…Among the result of PPI network, AR and ESR1 are associated with a variety of human behaviors, including anxiety [30]. PPARG has been con rmed to be associated with pathological anxiety [31]. glucocorticoid receptor (NR3C1) [32] and HTR2A [33] are also associated with anxiety disorders.…”