PI3K/AKT signaling activation by roflumilast ameliorates rotenone-induced Parkinson’s disease in rats

Abstract

Parkinson’s disease (PD) is the second most common progressive age-related neurodegenerative disorder. Paramount evidence shed light on the role of PI3K/AKT signaling activation in the treatment of neurodegenerative disorders. PI3K/AKT signaling can be activated via cAMP-dependent pathways achieved by phosphodiesterase 4 (PDE4) inhibition. Roflumilast is a well-known PDE4 inhibitor that is currently used in the treatment of chronic obstructive pulmonary disease. Furthermore, roflumilast has been proposed as a favorable candidate for the treatment of neurological disorders. The current study aimed to unravel the neuroprotective role of roflumilast in the rotenone model of PD in rats. Ninety male rats were allocated into six groups as follows: control, rotenone (1.5 mg/kg/48 h, s.c.), L-dopa (22.5 mg/kg, p.o), and roflumilast (0.2, 0.4 or 0.8 mg/kg, p.o). All treatments were administrated for 21 days 1 h after rotenone injection. Rats treated with roflumilast showed an improvement in motor activity and coordination as well as preservation of dopaminergic neurons in the striatum. Moreover, roflumilast increased cAMP level and activated the PI3K/AKT axis via stimulation of CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling cascades. Roflumilast also caused an upsurge in mTOR and Nrf2, halted GSK-3β and NF-ĸB, and suppressed FoxO1 and caspase-3. Our study revealed that roflumilast exerted neuroprotective effects in rotenone-induced neurotoxicity in rats. These neuroprotective effects were mediated via the crosstalk between CREB/BDNF/TrkB and SIRT1/PTP1B/IGF1 signaling pathways which activates PI3K/AKT trajectory. Therefore, PDE4 inhibition is likely to offer a reliable persuasive avenue in curing PD via PI3K/AKT signaling activation. Graphical Abstract

Azilsartan Attenuates 3-Nitropropinoic Acid-Induced Neurotoxicity in Rats: The Role of IĸB/NF-ĸB and KEAP1/Nrf2 Signaling Pathways

“…The box was cleaned with 10% isopropyl alcohol and dried carefully for each animal to avoid any disturbing substances left by the previous animal. The following parameters were recorded for each animal during the 3 min assessment period [ 37 , 38 ]. The latency time: time passed until the animal decides to move from the starting point (the central area) measured in seconds.…”

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

“…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,…”

“…Therapy designed to improve glucose regulation with the activation of autophagy may reduce heart and liver mass [177], reduce cerebral interneuron progenitor cell survival [381], foster death of neurons [382][383][384], enhance memory loss [132,362,[385][386][387][388], and potentially injure mitochondria [46,50,178,197,220,235,343,366,[389][390][391][392]. Cellular protection with growth factors, such as EPO, requires a reduction in autophagy activation in combination with the mechanistic target of rapamycin (mTOR), protein kinase B (Akt), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian forkhead transcription factors [290,306,310,340,341,[343][344][345]362,[393][394][395][396][397][398][399].…”

“…In the absence of AMPK activity, cell senescence, cell death, and mitochondrial injury can ensue [3,137]. WISP1 controls the phosphorylation of AMPK by differentially limiting phosphorylation of tuberous sclerosis 2 (TSC2) at serine 1387 , a target of AMPK, and promoting phosphorylation of TSC2 at threonine 1462 , a target of Akt [103,300,310,345,396,490,501] that has been shown to mediate protection of pancreatic cells [502] and neuroprotection [60,455,503] through glucagon-like peptide-1 (GLP-1). This ability of WISP1 to target and control AMPK may improve cell survival and metabolic homeostasis [168] since AMPK at times can reduce oxidative stress, limit insulin resistance [369], and lower lipid accumulation [504].…”