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Translational stroke researchReview

08 May 2025

Crosstalk Between Signaling Stroke Cascade and Therapeutic Receptors PPAR-γ, ROCK, CB1R, and CB2R: From Mechanism to Therapies.

Abstract

Stroke remains a leading cause of disability and mortality worldwide, primarily due to the complex and multifaceted nature of its pathophysiology.

This review aims to provide a comprehensive and mechanistic understanding of the crosstalk between key signaling pathways activated during stroke and the therapeutic potential of specific receptors: PPAR-γ, ROCK, CB1R, and CB2R.

We delve into the intricate signaling cascades that occur post-stroke, including excitotoxicity, oxidative stress, and inflammation, highlighting the pivotal molecular players involved.

PPAR-γ, known for its neuroprotective and anti-inflammatory properties, emerges as a critical modulator in stroke therapy. ROCK, a central component in the Rho/ROCK pathway, is implicated in vascular and neuronal damage, making its inhibition a promising therapeutic strategy.

The roles of CB1R and CB2R within the endocannabinoid system are explored, with a focus on their dualistic nature in neuroprotection and neurotoxicity.

The review further examines the interconnectivity of these receptors within the stroke signaling network, proposing that their synergistic modulation could enhance therapeutic outcomes.

Current therapeutic approaches, including pharmacological and multi-target strategies, are critically evaluated, addressing the challenges in translating mechanistic insights into clinical practice.

Additionally, the identification and utilization of biomarkers for stroke diagnosis and therapy monitoring are discussed, offering a glimpse into future prospects.

Emerging therapies, novel drug developments, and personalized medicine approaches are presented as potential game-changers in stroke treatment.

COI Statement

Declarations. Ethics approval: This study did not require ethical approval as it did not involve human or animal subjects Competing interest: The authors declare no competing interests.

References:

  • Kuriakose D, Xiao Z. Pathophysiology and Treatment of Stroke: Present Status and Future Perspectives. Int J Mol Sci. 2020;21:7609.
  • Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin. 2009;30:379.
  • Cai W, Yang T, Liu H, Han L, Zhang K, Hu X, et al. Peroxisome proliferator-activated receptor γ (PPARγ): A master gatekeeper in CNS injury and repair HHS Public Access. Prog Neurobiol. 2018;27–58.
  • Qin C, Yang S, Chu Y-H, Zhang H, Pang X-W, Chen L, et al. Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions.
  • Bietar B, Tanner S, Lehmann C. Neuroprotection and Beyond: The Central Role of CB1 and CB2 Receptors in Stroke Recovery. Int J Mol Sci. 2023;2023:16728.

Article info

Journal issue:

  • Volume: not provided
  • Issue: not provided

Doi:

10.1007/s12975-025-01352-2

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