Neuroprotective and oligodendrocyte precursor cell differentiation promoting activities of the RXR nuclear receptor agonist IRX4204 are potentiated by thyroid hormone
Authors: Martin Sanders, MD; Robin Avila, PhD; Bruce Trapp, PhD; Satish Medicetty, PhD; Rosh Chandraratna, PhD
Objective: (1) determine if the RXR nuclear receptor agonist IRX4204 is effective in an in vivo neuroprotection (NP) model; (2) evaluate the effects of combination treatment with thyroid hormone and IRX4204 in this model; (3) determine if adding thyroid hormone increases the previously reported stimulatory effect of IRX4204 on in vitro differentiation of oligodendrocyte precursor cells (OPC) into oligodendrocytes (OL).
Background: IRX4204 is a potent, highly selective RXR agonist compound being developed for treatment of multiple sclerosis (MS) and other neurologic diseases. Central hypothyroidism is a documented side effect of treatment with RXR agonists, including IRX4204. Since thyroid hormone is critical for CNS functions, we studied the effects of combination treatment with IRX4204 and thyroid hormone in an in vivo model of NP, and on OPC differentiation in vitro.
Design/Methods: Mice were administered cuprizone to induce demyelination; and rapamycin to prevent remyelination. NP was assessed by quantitation of SMI-32 immunostained axonal ovoids (transected axons) in the corpus callosum. Quantitation of OPC differentiation was performed by high-content screening of OPCs, which express PLP-EGFP when differentiated into OL; and by MBP immunostaining.
Results: Combination treatment with thyroid hormone and IRX4204 in the NP model resulted in reduction in axonal transection compared to vehicle, and approximately three-fold greater, statistically significant reduction compared to IRX4204 alone (-38.3% vs -13.6%). Addition of thyroid hormone with IRX4204 to OPC cultures resulted in statistically significant additive increase in myelin producing OL versus IRX4204 alone.
Conclusions: IRX4204 demonstrated neuroprotective effects in vivo; and OPC differentiation promoting effects in vitro; both of which were potentiated by thyroid hormone. RXR agonists should be co-administered with thyroid hormone, not only to maintain euthyroid status, but also to obtain improved efficacy in MS and other neurologic diseases patients treated with these agents.
Study Supported By: Supported by The National Multiple Sclerosis Society Fast Forward Program
However it is not only demyelination that occurs ans as we have been anticipating the is immunosuppressive. You can see the poster presentated at the AAN (click)
This means it does every thing which could mean that trials could be uninterpretable if they are not done carefully.