Addressing Peroxisome Proliferator-Activated Receptor-gamma in 3-Nitropropionic Acid-Induced Striatal Neurotoxicity in Rats

Abstract

Telmisartan (TEL) is an angiotensin II type 1 receptor blocker and a partial activator of peroxisome proliferator-activated receptor-gamma (PPARγ), which regulates inflammatory and apoptotic pathways. Increasing evidence has demonstrated the PPARγ agonistic property of TEL in several brain disorders. This study aims to explore the neuroprotective impact of TEL in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats. The PPARγ effect of TEL was affirmed by using the PPARγ agonist pioglitazone (PIO), and the antagonist GW9662. 3-NP led to a significant reduction in body weight alongside motor and cognitive functioning. The striata of the 3-NP-treated rats showed energy-deficit, microglia-mediated inflammatory reactions, apoptotic damage as well as histopathological lesions. PIO and TEL improved motor and cognitive perturbations induced by 3-NP, as confirmed by striatal histopathological examination, energy restoration, and neuronal preservation. Both drugs improved mitochondrial biogenesis evidenced by elevated mRNA expression of PPARγ, PGC-1α, and TFAM, alongside increased striatal ATP and SDH. The mitochondrial effect of TEL was beyond PPARγ activation. As well, their anti-inflammatory effect was attributed to suppression of microglial activation, and protein expression of pS536 p65 NF-κB with marked attenuation of striatal inflammatory mediator's release. Anti-inflammatory cytokine IL-10 expression was concurrently increased. TEL effectively participated in neuronal survival as it promoted phosphorylation of Akt/GSK-3β, further increased Bcl-2 expression, and inhibited cleavage of caspase-3. Interestingly, co-treatment with GW9662 partially revoked the beneficial effects of TEL. These findings recommend that TEL improves motor and cognitive performance, while reducing neuronal inflammation and apoptosis in 3-NP-induced neurotoxicity via a PPARγ-dependent mechanism. Graphical Abstract

Cognitive Impairment in Multiple Sclerosis

“…Recent studies have identified a significant role for pathways of programmed cell death that can ultimately control cell survival and cognitive impairment during MS [46,61,128,130,132,134,[200][201][202] (Table 1). Programmed cell death pathways that involve autophagy, apoptosis, pyroptosis, and ferroptosis can influence cell survival during inflammation [34,39,66,73,74,85,87,[203][204][205][206][207][208][209][210][211][212][213], oxidative stress [10,45,77,86,89,93,119,185,[214][215][216][217][218][219], ischemia [219][220][221][222][223], and mitochondrial dysfunction [32,…”

“…However, the loss of membrane PS asymmetry is reversible, and if membrane asymmetry is restored, injured cells are then given the ability to recover, and not be engulfed by inflammatory cells [197,[270][271][272]. With the later phase that involves deoxyribonucleic acid (DNA) degradation in the cell [34,40,77,226,[273][274][275], caspase activation plays a prominent role [15,77,194,206,210,273,[276][277][278]. This process of caspase activation and DNA destruction is irreversible [259].…”

Cornerstone Cellular Pathways for Metabolic Disorders and Diabetes Mellitus: Non-Coding RNAs, Wnt Signaling, and AMPK

“…If the second phase of apoptotic cell death is reached, it is usually not reversible and involves the degradation of nuclear deoxyribonucleic acid (DNA) [136,137,167,169,[290][291][292][293][294]. The second stage of apoptosis consists of mitochondrial membrane depolarization, cytochrome c release, and caspase activation [136,193,252,290,[295][296][297][298][299][300]. Apoptosis during DM can lead to atherosclerotic plaque generation [296,301,302], foster processes associated with infection, such as COVID-19 [59,71,303,304], promote joint degenerative diseases [152,293,[305][306][307], and enhance stem cell demise and inflammatory pathway activation [26,103,129,132,291,[308][309][310][311][312][313][314].…”

“…Apoptosis during metabolic disorders also can be involved in adipose tissue inflammation during loss of metabolic homeostasis [315], may lead to cognitive loss in combination with autophagic pathways [77], promote microglial activation to the detriment of cells [26], impair pancreatic β-cell function [61,316], promote demyelination of nerve fibers [317], lead to ischemic cell injury [63], result in retinal cell loss [75,76,292,[318][319][320][321], foster renal cell injury [43,220,322], and lead to vascular cell degeneration [53, 101,215,277,323]. In particular, microglia are important for removing damaged cells during membrane PS externalization and apoptosis [106,131,145,277,278,298,308,[324][325][326][327]]. Yet, microglia can lead to the generation of oxidative stress through the production of ROS [8,165,167,246,250,[328][329][330][331], which can require modulation by non-coding RNAs [251,[332]…”

Microglial Pdcd4 deficiency mitigates neuroinflammation-associated depression via facilitating Daxx mediated PPARγ/IL-10 signaling

“…Based on the fact that neuronal PPARγ knockout in the prefrontal cortex of mice induces depressive-like behavior, PPARγ agonist, rosiglitazone, has an antidepressant-like effect on stressed mice [12][13][14]. The activation of PPARγ inhibits in ammatory response via increasing anti-in ammatory cytokines expression or suppressing pro-in ammatory molecules, which contributes to injured brain repairment [15,16]. However, the role of microglial PPARγ in emotional behavior is still unclear.…”