Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups.

Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased cerebellar EGL proliferation and Purkinje cell maturation. The preterm rabbit pup model exhibits important characteristics of human preterm birth, and may thus be suitable for the evaluation of interventions aiming to modify growth and cerebellar development in the preterm population.

Cerebellar Exposure to Cell-Free Hemoglobin Following Preterm Intraventricular Hemorrhage: Causal in Cerebellar Damage?

Decreased cerebellar volume is associated with intraventricular hemorrhage (IVH) in very preterm infants and may be a principal component in neurodevelopmental impairment. Cerebellar deposition of blood products from the subarachnoid space has been suggested as a causal mechanism in cerebellar underdevelopment following IVH. Using the preterm rabbit pup IVH model, we evaluated the effects of IVH induced at E29 (3 days prior to term) on cerebellar development at term-equivalent postnatal day 0 (P0), term-equivalent postnatal day 2 (P2), and term-equivalent postnatal day 5 (P5). Furthermore, the presence of cell-free hemoglobin (Hb) in cerebellar tissue was characterized, and cell-free Hb was evaluated as a causal factor in the development of cerebellar damage following preterm IVH. IVH was associated with a decreased proliferative (Ki67-positive) portion of the external granular layer (EGL), delayed Purkinje cell maturation, and activated microglia in the cerebellar white matter. In pups with IVH, immunolabeling of the cerebellum at P0 demonstrated a widespread presence of cell-free Hb, primarily distributed in the white matter and the molecular layer. Intraventricular injection of the Hb scavenger haptoglobin (Hp) resulted in a corresponding distribution of immunolabeled Hp in the cerebellum and a partial reversal of the damaging effects observed following IVH. The results suggest that cell-free Hb is causally involved in cerebellar damage following IVH and that blocking cell-free Hb may have protective effects.

Inhibition of the development of chronic experimental autoimmune encephalomyelitis by laquinimod (ABR-215062) in IFN-beta k.o. and wild type mice.

Laquinimod is a novel oral immunomodulatory substance, which is currently developed for the treatment of multiple sclerosis (MS). The ability of laquinimod to inhibit disease development was investigated in chronic experimental autoimmune encephalomyelitis (chEAE) in IFN-beta k.o. mice and wild type mice. Laquinimod was shown to inhibit both disease development and histopathological changes in the CNS. Furthermore, laquinimod was found to be independent of endogenous IFN-beta for its effect in chEAE. When laquinimod was combined with exogenous IFN-beta, a synergistic disease inhibitory effect was seen. These findings using laquinimod in preclinical disease models for MS emphasize the potential of laquinimod in the future treatment of MS also in patients that do not respond to IFN-beta monotherapy. Furthermore, the results indicate that laquinimod may favourably be combined with IFN-beta.

The new orally active immunoregulator laquinimod (ABR-215062) effectively inhibits development and relapses of experimental autoimmune encephalomyelitis.

A new orally active drug, laquinimod (ABR-215062), was shown to completely inhibit the development of murine acute experimental autoimmune encephalomyelitis (EAE). Furthermore, leukocyte infiltration into the central nervous system (CNS) was abolished in the laquinimod-treated animals. By direct comparison based on dose and total exposure, laquinimod was approximately 20 times more potent than the immunomodulator roquinimex. Laquinimod also had clear therapeutic effect when given after clinical onset in a chronic relapsing EAE model. It therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties for the treatment of the autoimmune disease multiple sclerosis.

Linomide inhibits insulitis and modulates cytokine production in pancreatic islets in the nonobese diabetic mouse.

Linomide is an immunomodulator which has been shown to potently inhibit autoimmunity in several animal models for human autoimmune diseases, including type I diabetes in the nonobese diabetic (NOD) mouse. In this study, we investigate the basis for Linomide's protective effects in the NOD mouse by immunohistochemical and RT-PCR analysis of the phenotype and cytokine expression by cells infiltrating the islets of Langerhans in the pancreas. Linomide treatment was found to reduce the infiltration of T cells, B cells, dendritic cells (DC) and MHC class II(+) cells into the islets, but did not reduce macrophage (MPhi) infiltration. This was seen following Linomide treatment at 3-5, 4-8 and 14-24 weeks of age and thus appears to be independent of the stage of the autoreactive process and the extent of insulitis. The reduced insulitis may be due to reduced expression of adhesion molecules since decreased numbers of islet-associated blood vessels expressing CD106 and MAdCAM-1 were detected following Linomide treatment. Furthermore, short term Linomide treatment (3 or 7 days), which did not alter the number of infiltrating cells, was found to inhibit the production of TNF-alpha which is known to induce the expression of CD106 and MAdCAM-1. These results suggest that the reduced insulitis observed in Linomide-treated animals is secondary to a functional modulation of infiltrating cells.