The selective glucocorticoid receptor modulator CORT108297 restores faulty hippocampal parameters in Wobbler and corticosterone-treated mice

MEYER M; GONZALEZ DENISELLE MC; HAZEL HUNT; DE KLOET ER; DE NICOLA A. F.

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY

PERGAMON-ELSEVIER SCIENCE LTD

Lugar: Amsterdam; Año: 2014 vol. 143 p. 40 - 48

0960-0760

Mutant Wobbler mice are models for human amyotrophiclateral sclerosis (ALS). In addition to spinal cord degeneration, Wobbler miceshow high levels of blood corticosterone, hyperactivity of thehypothalamic?pituitary?adrenal axis and abnormalities of the hippocampus.Hypersecretion of gluco- corticoids increase hippocampus vulnerability, aprocess linked to an enriched content of glucocorticoid receptors (GR). Hence,we studied if a selective GR antagonist (CORT108297) with null affinity forother steroid receptors restored faulty hippocampus parameters of Wobbler mice.Three months old geno- typed Wobbler mice received s.c. vehicle or CORT108297during 4 days. We compared the response of doublecortin (DCX)+ neuroblasts inthe subgranular layer of the dentate gyrus (DG), NeuN+ cells in the hilus ofthe DG, glial fibrillary acidic protein (GFAP)+ astrocytes and the phenotype ofIba1+ microglia in CORT108297-treated and vehicle-treated Wobblers. The numberof DCX+ cells in Wobblers was lower than in control mice, whereas CORT108297restored this parameter. After CORT108297 treatment, Wob- blers showeddiminished astrogliosis, and changed the phenotype of Iba1+ microglia from anactivated to a quiescent form. These changes occurred without alterations inthe hypercorticosteronemia or the number of NeuN+ cells of the Wobblers. In aseparate experiment employing control NFR/NFR mice, treatment with corticosteronefor 5 days reduced DCX+ neuroblasts and induced astrocyte hypertrophy, whereastreatment with CORT108297 antagonized these effects. Normalization of neuronalprogenitors, astrogliosis and microglial phenotype by CORT108297 indicates theusefulness of this antagonist to nor- malize hippocampus parameters of Wobblermice. Thus, CORT108297 opens new therapeutic options for the brainabnormalities of ALS patients and hyperadrenocorticisms