Premature birth is very strongly associated with maternal/foetal inflammation and leads to permanent neurological deficits correlated with white matter damage, including maturational arrest of oligodendrocytes and hypomyelination. Preterm birth and exposure to inflammation causes hypothyroxinemia, and as oligodendrocyte maturation and myelination is regulated by thyroid hormones, supplementation with thyroxine (T4) seems a good candidate therapy for reducing white matter damage in preterm infants.
We report on a model of preterm inflammation-induced white matter damage, in which exposure from P1 to P5 to systemic inflammation, induced by interleukin-1β (IL-1β) causes oligodendrocyte maturational arrest and hypomyelination. In this model we have identified a transient hypothyroidism and wide-ranging dysfunction in thyroid hormone signalling pathways. To test whether a clinically relevant dose of T4 could reduce inflammation-induced white matter damage we concurrently treated mice being exposed to IL-1β from P1-P5 with T4 (20µg/kg/injection). At P10 we isolated O4-positive pre-oligodendrocytes, and gene expression analysis revealed that T4 treatment did not recover the IL-1β-induced maturational blockade of oligodendrocyte maturation. Moreover, at P10 and P30 immunohistochemistry for markers of oligodendrocyte lineage (NG2, PDGFRα and APC) and myelin (MBP) similarly indicated that T4 treatment did not improve IL-1β-induced deficits in the white matter.
In summary, in this model of preterm inflammation-induced white matter injury a clinically relevant dose of T4 had no therapeutic efficacy. We suggest that additional pre-clinical trials with T4 covering the breadth and scope of causes and outcomes of perinatal brain injury are required before we can correctly evaluate clinical trials data and understand the potential for thyroid hormone as a widely implementable clinical therapy.