PPAR Agonist Development for Stroke

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and are key regulators of glucose and lipid metabolism. Many in vivo and in vitro studies have shown that activation of all three PPAR isoforms, especially PPAR-γ, limits postischemic injury. PPAR-γ acts by a variety of mechanisms, including the activation of multiple protective pathways associated with inflammation, apoptosis, blood-brain barrier protection, neurogenesis, and oxidative stress. PPAR, as a modulator of CNS inflammation, is a potent pharmacological target to combat neurodegeneration, which has been demonstrated in animal models of stroke.

Fig.1. Summary of basic mechanisms of individual PPAR receptors and downstream pathways in stroke. (Gamdzyk, et al., 2020)

Our PPAR Agonist Development Services for Stroke

Ace Therapeutics has extensive experience in the field of stroke. We can help our clients analyze the role of different subtypes of PPAR (α, β/δ, and γ) in stroke and develop stroke drugs targeting PPARs. Our laboratories are equipped with advanced tools for molecular analysis, cell culture studies, and animal experiments to support the entire PPAR agonist development process. Our team of experts conducts comprehensive, high-quality studies to ensure reliable data and accurate results.

Design and Optimization of PPAR Agonists

• The first step is to determine which PPAR isoform (PPAR-α, PPAR-γ, or PPAR-β/δ) to target for agonist development.
• Using the crystal structure model of the PPAR protein, we can screen the candidate compounds by molecular docking technique and predict their binding affinity and binding modes to target proteins.
• Constructing of three-dimensional pharmacophore models of PPAR binding based on the structural features of known PPAR agonists.
• Developing quantitative mathematical models of the relationship between PPAR agonist activity and molecular descriptors to guide compound optimization.
• Providing targeted structural modifications to optimize the affinity, selectivity, and pharmacokinetic properties of the compounds.
• Utilizing bioisomer substitution, linkage construction, and other methods to enhance the activity and durability of compounds.

In Vitro Analysis of PPAR Agonists

We use primary cultured cortical neurons or hippocampal neurons to mimic hypoxia/reperfusion injury. We offer a series of cell-based analyses to assess the protective effects of PPAR agonists on neuronal cells.

• MTT or CCK-8 assays to assess cell proliferation and survival.
• LDH release assay to detect cell membrane damage and reflect cytotoxicity.
• TUNEL or Annexin V/PI staining to detect cell apoptosis.
• Detection of ROS/RNS levels: e.g., DCFH-DA probe, MitoSOX red dye.
• Detection of mitochondrial membrane potential: e.g., JC-1 dye.

In Vivo Analysis of PPAR Agonists

We offer validated animal models of ischemic stroke to evaluate the efficacy and safety of PPAR agonists. We perform multiple assessment indices to comprehensively analyze the neuroprotective, anti-inflammatory and antioxidant mechanisms of PPAR agonists in animal models of stroke, providing important experimental data for preclinical studies.

• Behavioral tests: e.g., spinning test, balance beam test.
• TTC staining or MRI imaging to measure cerebral infarct volume.
• Cerebral edema: Measurement of wet weight/dry weight ratio or water content.
• Blood-brain barrier permeability: By detecting leakage of exogenous tracers (e.g., EB or HRP).
• Detection of drug binding to PPAR in vivo.
• Detection of changes in PPAR expression levels.

At Ace Therapeutics, we actively seek collaborations with pharmaceutical companies and academic institutions. By leveraging our collective expertise and resources, we can accelerate the development of PPAR agonists for the treatment of stroke. If you are interested in our services, please do not hesitate to contact us!

1. Gamdzyk, M., et al. (2020). Role of peroxisome proliferator‐activated receptors in stroke prevention and therapy—The best is yet to come?. Journal of Neuroscience Research, 98(11), 2275-2289.