Failure of thyroid hormone treatment to prevent inflammation-induced white matter injury in the immature brain.
Preterm birth is very strongly associated with maternal/foetal inflammation and leads to permanent neurological deficits. These deficits correlate with the severity of white matter injury, including maturational arrest of oligodendrocytes and hypomyelination. Preterm birth and exposure to inflammation causes hypothyroxinemia. As such, supplementation with thyroxine (T4) seems a good candidate therapy for reducing white matter damage in preterm infants as oligodendrocyte maturation and myelination is regulated by thyroid hormones. We report on a model of preterm inflammation-induced white matter damage, in which induction of systemic inflammation by exposure from P1 to P5 to interleukin-1β (IL-1β) causes oligodendrocyte maturational arrest and hypomyelination. This model identified 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 exposed to IL-1β from P1 to P5 with T4 (20 μg/kg/day). At P10, we isolated O4-positive pre-oligodendrocytes and gene expression analysis revealed that T4 treatment did not recover the IL-1β-induced 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 recover IL-1β-induced deficits in the white matter. In summary, in this model of preterm inflammation-induced white matter injury, a clinical 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.
Inserm U676, 75019 Paris, France; Université Paris Diderot, Faculté de Médecine, 75019 Paris, France; PremUP, 75014 Paris, France.
Anne-Laure
AL
Schang
Inserm U676, 75019 Paris, France; Université Paris Diderot, Faculté de Médecine, 75019 Paris, France; PremUP, 75014 Paris, France.
Juliette
J
Van Steenwinckel
Service de biochimie et hormonologie, Hôpital Robert Debré, 75019 Paris, France.
Didier
D
Chevenne
Department of Clinical Sciences, Sahlgrenska Academy/East Hospital, 416 85 Gothenburg, Sweden.
Marten
M
Alkmark
Department of Clinical Sciences, Sahlgrenska Academy/East Hospital, 416 85 Gothenburg, Sweden; Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
Henrik
H
Hagberg
Inserm U676, 75019 Paris, France; Université Paris Diderot, Faculté de Médecine, 75019 Paris, France; PremUP, 75014 Paris, France; Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom. Electronic address: pierre.gressens@inserm.fr.
Pierre
P
Gressens
Inserm U676, 75019 Paris, France; Université Paris Diderot, Faculté de Médecine, 75019 Paris, France; PremUP, 75014 Paris, France; Department of Perinatal Imaging and Health, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London SE1 7EH, United Kingdom.
Bobbi
B
Fleiss
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000254:growth & development; D004195:Disease Models, Animal; D004660:Encephalitis / Q000517:prevention & control*; D015870:Gene Expression; D053583:Interleukin-1beta / Q000633:toxicity; D008297:Male; D051379:Mice; D009413:Nerve Fibers, Myelinated / Q000187:drug effects* / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects*; D013974:Thyroxine / Q000627:therapeutic use*
D053583:Interleukin-1beta; D013974:Thyroxine
Myelination; Neuroprotection; Oligodendrocyte; Prematurity; Thyroxine