The Neuroprotective Mechanisms of PPAR‐γ: Inhibition of Microglia‐Mediated Neuroinflammation and Oxidative Stress in a Neonatal Mouse Model of Hypoxic‐Ischemic White Matter Injury DOI Creative Commons
Mingchu Fang, Qianqian Yu, J T Ou

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2024, Volume and Issue: 30(11)

Published: Nov. 1, 2024

ABSTRACT Background Neuroinflammation and oxidative stress, mediated by microglial activation, hinder the development of oligodendrocytes (OLs) delay myelination in preterm infants, leading to white matter injury (WMI) long‐term neurodevelopmental sequelae. Peroxisome proliferator‐activated receptor gamma (PPAR‐γ) has been reported inhibit inflammation stress via modulating polarization various central nervous system diseases. However, relationship between PPAR‐γ neonatal WMI is not well understood. Therefore, this study aimed elucidate role mechanisms infants affected WMI. Methods In study, an vivo hypoxia‐ischemia (HI) induced brain mouse model was established. The mice were administered intraperitoneally with either RSGI or GW9662 activate PPAR‐γ, respectively. Additionally, vitro oxygen–glucose deprivation (OGD) cell established pretreated pcDNA 3.1‐PPAR‐γ si‐PPAR‐γ overexpress silence neuroprotective effects investigated vivo. Firstly, open field test, novel object recognization beam‐walking test employed assess on neurobehavioral recovery. Furthermore, assessment OLs loss OL‐maturation disorder, number myelinated axons, myelin thickness, synaptic deficit, activation microglia astrocyte, blood–brain barrier (BBB) used evaluate pathological repair. explored both vitro. Assessment polarization, inflammatory mediators, reactive oxygen species (ROS), MDA, antioxidant enzymes anti‐inflammatory antioxidative activation. An HMGB1/NF‐κB NRF2/KEAP1 signaling pathway conducted clarify which influences HI‐induced mice. Results Activation using significantly mitigated BBB disruption, promoted M2 microglia, inhibited astrocytes, development, enhanced Conversely, inhibition further exacerbated pathologic hallmark Neurobehavioral tests revealed that neurological deficits ameliorated RSGI, while aggravated GW91662. addition, alleviated neuroinflammation suppressing activating NRF2 HI OGD‐induced neuroinflammation, modulation same pathway. Conclusions Our findings suggest regulates activation/polarization as subsequent neuroinflammation/oxidative pathway, thereby contributing neuroprotection amelioration

Language: Английский

Pioglitazone mitigates acetic acid-induced colitis in rats via epigenetic-modulation and antioxidant mechanisms DOI
Suzan Awad AbdelGhany Morsy, Lobna Abd El Mottelib, Sara Assem

et al.

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Language: Английский

Citations

0
The possible role of neurogenesis activators in temporal lobe epilepsy: State of art and future perspective DOI Creative Commons

Ahmed Salem Al-Dhahi,

Hayder M. Al‐kuraishy,

Ali K. Albuhadily

et al.

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177646 - 177646

Published: April 1, 2025

Neurogenesis is a complex process by which the neurons and supporting cells of central nervous system (CNS) are generated neural stem cells. Adult hippocampal neurogenesis (AHN) in human brain an active during life plays critical role regulation memory, cognition, mood. It has been shown that epilepsy linked with dysregulation AHN. Of note, AHN very sensitive to pathological electrical stimuli epileptic seizures, result induction acute inhibition chronic epilepsy. Epileptic seizure-induced neurodegeneration activates mobilization substitute for loss temporal lobe (TLE), most refractory type Moreover, recurrent seizures TLE trigger certain regions. However, transient seizure terminated 1-4 weeks following status epilepticus (SE). Nevertheless, adult dramatically reduced associated development cognitive impairment TLE. These findings indicate severity seizures. Hence, activators may attenuate pathogenesis Therefore, this review aims discuss explain beneficial how could be effective management

Language: Английский

Citations

0
Unlocking the Neuroprotective Effect of Quercetin Against Cadmium-Induced Hippocampal Damage in Rats: PPARγ Activation as a Key Mechanism DOI Creative Commons
Doha M. Al-Nouri

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(5), P. 657 - 657

Published: April 29, 2025

Background: This study investigates the effects of cadmium chloride (CdCl2) on hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) expression and examines whether PPARγ activation mediates neuroprotective quercetin (QUR). Methods: Sixty adult male rats were included in this study, separated into 12 per group as follows: control, CdCl2 (0.5 mg/kg), + agonist (Pioglitazone, 10 QUR (25 antagonist (GW9662, 1 mg/kg). Treatments administered orally for 30 days. At end experiment, behavioral memory tests, histology, markers cholinergic function, neuroplasticity, oxidative stress, inflammation, apoptosis, well transcription levels some genes carried out. Results: exposure significantly reduced mRNA DNA binding potential nuclear levels. Additionally, impaired spatial, short-term, recognition memory, decreased granular cell density dentate gyrus (DG), factors, including Nrf2, brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), several antioxidant enzymes heme-oxygenase-1 (HO-1) superoxide dismutase (SOD), glutathione (GSH). Conversely, elevated apoptosis such interleukin-6 (IL-6), malondialdehyde (MDA), Bax, tumor necrosis factor-α (TNF-α), cleaved caspase-3. Pioglitazone reversed these effects, restoring activation, improving modulating anti-inflammatory pathways. In contrast, blocking with GW9662 negated QUR, exacerbating stress inflammation by reversing all their beneficial effects. Conclusions: Activation or offers a promising therapeutic strategy mitigating CdCl2-induced neurotoxicity.

Language: Английский

Citations

0
Structural Biology Inspired Development of a Series of Human Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Ligands: From Agonist to Antagonist DOI Open Access
Hiroyuki Miyachi

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3940 - 3940

Published: Feb. 15, 2023

Recent progress in the structural and molecular pharmacological understanding of nuclear receptor, peroxisome proliferator-activated receptor gamma (hPPARγ)—a transcription factor with pleiotropic effects on biological responses—has enabled investigation various graded hPPARγ ligands (full agonist, partial antagonist). Such are useful tools to investigate functions detail also candidate drugs for treatment hPPARγ-mediated diseases, such as metabolic syndrome cancer. This review summarizes our medicinal chemistry research design, synthesis, evaluation a covalent-binding non-covalent-binding antagonist, both which have been created based working hypothesis helix 12 (H12) holding induction/inhibition concept. X-ray crystallographic analyses representative antagonists complexed an ligand binding domain (LBD) indicated unique modes LBD, quite different from observed agonists agonists.

Language: Английский

Citations

10
An Overview of the Role of Peroxisome Proliferator-activated Receptors in Liver Diseases DOI Open Access
Zahra Changizi, Forough Kajbaf, Azam Moslehi

et al.

Journal of Clinical and Translational Hepatology, Journal Year: 2023, Volume and Issue: 11(7), P. 1542 - 1552

Published: Nov. 15, 2023

Peroxisome proliferator-activated receptors (PPARs) are a superfamily of nuclear transcription receptors, consisting PPARα, PPARγ, and PPARβ/δ, which highly expressed in the liver. They control modulate expression large number genes involved metabolism energy homeostasis, oxidative stress, inflammation, even apoptosis Therefore, they have critical roles pathophysiology hepatic diseases. This review provides general insight into role PPARs liver diseases some their agonists clinic.

Language: Английский

Citations

10
Evidence from an Avian Embryo Model that Zinc-Inducible MT4 Expression Protects Mitochondrial Function Against Oxidative Stress DOI Creative Commons
Hao Li, Wei Gao, Heng Wang

et al.

Journal of Nutrition, Journal Year: 2024, Volume and Issue: 154(3), P. 896 - 907

Published: Feb. 1, 2024

Language: Английский

Citations

3
Exploring the molecular mechanisms of PPARγ agonists in modulating memory impairment in neurodegenerative disorders DOI
Yousef Baghcheghi,

Fateme Razazpour,

Fatemeh Seyedi

et al.

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: Aug. 31, 2024

Language: Английский

Citations

3
Conquering Insulin Network Dysfunctions in Alzheimer’s Disease: Where Are We Today? DOI

Suzanne M. de la Monte

Journal of Alzheimer s Disease, Journal Year: 2024, Volume and Issue: 101(s1), P. S317 - S343

Published: Oct. 18, 2024

Functional impairments in the brain's insulin and insulin-like growth factor (IGF) signal transduction networks are recognized mediators of dysregulated energy metabolism, a major driver Alzheimer's disease (AD) neurodegeneration cascade. AD-associated insulin-deficient insulin-resistant states mimic those diabetes mellitus affect all cell types brain. Besides accounting for abundant amyloid-β hyperphosphorylated tau lesions AD, insulin/IGF pathway dysfunctions cause cortical atrophy, loss synaptic plasticity, white matter myelin/oligodendrocyte degeneration, astrocyte microglial neuroinflammation oxidative stress, deficits mitochondrial dysfunction, microvascular disease. These same neuropathological processes have been linked to cognitive impairment type 2 mellitus, Parkinson's disease, vascular dementia. Strategies address metabolic borrowed from other diseases leveraged on preclinical AD model data. The repurposing drugs led clinical trials with intranasal insulin, followed by sensitizers including metformin peroxisome-proliferator-activated receptor agonists, then incretin mimetics primarily targeting GLP-1 receptors. In addition, glucose-lowering agents tested their efficacy preventing declines. strengths limitations these approaches discussed. main conclusion this review is that we now arrived at stage which it time long-term trophic availability responsiveness, signaling abnormalities extend beyond include IGFs interconnected pathways, need multi-pronged rather than single-pronged therapeutic remediate forms neurodegeneration.

Language: Английский

Citations

3
Anti-diabetic agents and the risks of dementia in patients with type 2 diabetes: a systematic review and network meta-analysis of observational studies and randomized controlled trials DOI Creative Commons
Zonglin Li, Chu Lin, Xiaoling Cai

et al.

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: Dec. 23, 2024

To evaluate the association between anti-diabetic agents and risks of dementia in patients with type 2 diabetes (T2D). Literature retrieval was conducted PubMed, Embase, Cochrane Central Register Controlled Trials Clinicaltrial.gov January 1995 October 2024. Observational studies randomized controlled trials (RCTs) T2D, which intercompared or compared them placebo, reported incidence were included. Conventional network meta-analyses these implemented. Results exhibited as odds ratio (OR) risk (RR) 95% confidence interval (CI). A total 41 observational (3,307,483 participants) 23 RCTs (155,443 In meta-analysis studies, non-users, sodium glucose cotransporter-2 inhibitor (SGLT-2i) (OR = 0.56, 95%CI, 0.45 to 0.69), glucagon-like peptide-1 receptor agonist (GLP-1RA) 0.58, 0.46 0.73), thiazolidinedione (TZD) 0.68, 0.57 0.81) metformin 0.89, 0.80 0.99) treatments all associated reduced T2D. The surface under cumulative ranking curve (SUCRA) evaluation conferred a rank order SGLT-2i > GLP-1RA TZD dipeptidyl peptidase-4 (DPP-4i) α-glucosidase (AGI) glucokinase activator (GKA) sulfonylureas glinides insulin terms cognitive benefits. Meanwhile, 0.43, 0.30 0.62), 0.54, 0.96) DPP-4i 0.73, 0.93) Alzheimer's disease while lower vascular observed receiving 0.42, 0.22 0.80) 0.52, 0.36 0.75) treatment. RCTs, comparable among placebo. Compared SGLT-2i, GLP-1RA, may serve optimal choice improve prognosis

Language: Английский

Citations

3
The Ameliorative Effect of Pioglitazone against Neuroinflammation Caused by Doxorubicin in Rats DOI Creative Commons

May M. Alsaud,

Ahmad Alhowail, Maha A. Aldubayan

et al.

Molecules, Journal Year: 2023, Volume and Issue: 28(12), P. 4775 - 4775

Published: June 15, 2023

Doxorubicin (DOX) is a chemotherapeutic agent that linked with complications such as cardiotoxicity and cognitive dysfunction, known chemobrain. Chemobrain affects up to 75% of cancer survivors, there are no therapeutic options for its treatment. This study aimed determine the protective effect pioglitazone (PIO) against DOX-induced impairment. Forty Wistar female rats were equally divided into four groups: control, DOX-treated, PIO-treated, DOX + PIO-treated. was administered at dose 5 mg/kg, i.p., twice week two weeks (cumulative dose, 20 mg/kg). PIO dissolved in drinking water concentration 2 mg/kg DOX-PIO groups. The survival rates, change body weight, behavioral assessment performed using Y-maze, novel object recognition (NOR), elevated plus maze (EPM), followed by estimation neuroinflammatory cytokines IL-6, IL-1β, TNF-α brain homogenate RT-PCR sample. Our results showed rate 40% 65% groups, respectively, compared 100% control treatment groups end day 14. There an insignificant increase weight group significant reduction DOX-treated animals exhibited impairment function, combination reversal evidenced changes TNF-α, IL-6 levels also mRNA expression TNF- α, IL-6. In conclusion, produced memory alleviating neuronal inflammation modulating inflammatory cytokines.

Language: Английский

Citations

9