Table 1.
Synthetic dual LXRα/β agonists in preclinical models of inflammatory disease*
| Disease model | LXR agonist | Effect | Reference |
|---|---|---|---|
| Autoimmune disease | |||
| Collagen-induced arthritis | GW3965 | ↓clinical and pathological severity | (Park, et al., 2010) |
| GW3965, T0901317 | ↑inflammation; ↑cartilage destruction | (Asquith, et al., 2009; Asquith, et al., 2011) | |
| Experimental autoimmune uveitis | T0901317 | ↓retinal cytokines; ↓clinical severity | (Yang, et al., 2014) |
| EAE (multiple sclerosis model) | T0901317 | ↓CNS inflammation, demyelination, clinical severity | (Cui, et al., 2011) |
| Lupus (lpr/lpr mouse) | GW3965 | ↓lymphadenopathy; ↓glomerular antibody deposition | (A-Gonzalez, et al., 2009) |
|
| |||
| Neurologic disease | |||
| Alzheimer’s disease (APP/PS1 tg) | T0901317 | ↓glial inflammation; ↓cognitive impairment | (Cui, et al., 2012) |
| (APP23) | T0901317 | ↓Aβ levels | (Terwel, et al., 2011) |
| Acute brain ischemia | GW3965 | ↓inflammation; ↓injury | (Sironi, et al., 2008) |
| GW3965, T0901317 | ↓infarct volume; ↓inflammation; ↑neurologic function | (Morales, et al., 2008) | |
| Cerebral hemorrhage | T0901317 | ↓inflammation; ↓brain damage; ↓functional deficits | (Wu, et al., 2016) |
| Spinal cord trauma | T0901317 | ↓inflammation; ↓tissue injury; ↑limb function | (Paterniti, et al., 2010) |
| MPTP-induced Parkinson’s disease | T0901317 | ↓ inflammation | (Paterniti, et al., 2017) |
|
| |||
| Lung disease | |||
| Acute lung injury (LPS) | T0901317 | ↓neutrophil recruitment, ↓airspace TNFα | (Smoak, et al., 2008) |
| Acute lung injury (bleomycin) | T0901317 | ↓inflammation; ↓fibrosis | (Shi, et al., 2016) |
| Asthma (OVA) | GW3965 | ↔ inflammation; ↔ mucus; ↑AHR; ↑ASM thickness | (Birrell, et al., 2008) |
| (OVA) | T0901317 | ↔ inflammation; ↓mucus; ↓IgE; ↓AHR; ↓ASM thickness | (Shi, et al., 2014) |
| (OVA, HDM) | GW3965 | ↑eosinophils; ↑T helper 2 cytokines | (Smet, et al., 2016) |
|
| |||
| Ischemia/reperfusion injury | |||
| Myocardial | GW3965 | ↓infarct size; ↓oxidative stress; ↓ventricular dysfunction | (He, et al., 2014) |
| Splanchnic | T0901317 | ↓neutrophil infiltration; ↓tissue injury; ↑survival | (Crisafulli, et al., 2010) |
|
| |||
| Miscellaneous | |||
| DSS- and TNBS-induced colitis | GW3965 | ↓inflammation; ↑body weight recovery; ↑survival | (Jakobsson, et al., 2014) |
| Diabetic nephropathy (STZ model) | T0901317 | ↓macrophage infiltration; ↓cytokines; ↓urinary albumin | (Tachibana, et al., 2012) |
| Renal transplantation | GW3965 | ↓graft inflammation and dysfunction | (Kiss, et al., 2011) |
| Irritant and allergic dermatitis | GW3965 | ↓skin thickness and inflammation | (Fowler, et al., 2003) |
*
This table lists select reports of GW3965 and TO901317 efficacy across preclinical inflammatory disease models.
AHR, airway hyperresponsiveness; APP, amyloid precursor protein; ASM, airway smooth muscle; DSS, dextran sulfate sodium; EAE, experimental autoimmune encephalomyelitis; HDM, house dust mite; Ig, immunoglobulin; LPS, lipopolysaccharide; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; OVA, ovalbumin sensitization and challenge; PS-1, presenilin-1; STZ, streptozotocin; tg, transgenic mouse; TNBS, 2,4,6-Trinitrobenzenesulfonic acid.