Bone Morphogenetic Protein Inhibition Promotes Neurological Recovery after Intraventricular Hemorrhage

Abstract

Intraventricular hemorrhage (IVH) results in neural cell-death and white matter injury in premature infants. No therapeutic strategy is currently available against this disorder. Bone-morphogenetic-protein (BMP) signaling suppresses oligodendrocyte development through basic-helix-loop-helix (bHLH) transcription factors and promotes astrocytosis. Therefore, we hypothesized that IVH in premature newborns initiates degeneration and maturation arrest of oligodendrocyte lineage, and that BMP inhibition alleviates hypomyelination, gliosis, and motor impairment in the survivors of IVH. To test the hypotheses, a rabbit model of IVH was used where premature rabbit pups (E29) are treated with intraperitoneal glycerol at 2 h age to induce IVH; and the pups with IVH exhibit hypomyelination and gliosis at two weeks of postnatal age. Maturation of oligodendrocyte lineage was evaluated by specific markers; and the expression of bHLH transcription factors was assessed. BMP levels were measured in both premature rabbit pups and autopsy materials from premature infants. Recombinant human noggin was used to suppress BMP action; and neurobehavioral performance, myelination and gliosis were assessed in noggin-treated pups compared to untreated controls. We found that IVH resulted in apoptosis and reduced proliferation of oligodendrocyte progenitors, as well as arrested maturation of pre-oligodendrocytes in rabbits. BMP4 levels were significantly elevated in both rabbit pups and human premature infants with IVH compared to controls. Importantly, BMP inhibition by recombinant human noggin restored the levels of phospho-Smad 1/5/8, Olig2 transcription factor, oligodendrocyte maturation, myelination, astrocyte morphology and motor function in premature pups with IVH. Hence, BMP inhibition might enhance neurological recovery in premature infants with IVH.

Mesenchymal Stem Cells Prevent Hydrocephalus After Severe Intraventricular Hemorrhage

“…These findings suggest that increased pressure attributable to progressive hydrocephalus after severe IVH might contribute to periventricular white matter injury and demyelination, as evidenced by corpus callosum thinning and reduced MBP expression. 33,34 In addition, the protective effects of MSC transplantation might be attributable, at least in part, to preventing PHH. The improved rotarod tests results at P31 and P32 after MSC transplantation imply that the protective effects might persist into human adolescence.…”

Nanomedicine in cerebral palsy

“…105 This may be dictated by ongoing inflammation in the brain, as evidenced by preclinical studies and postmortem studies in humans with periventricular leukomalacia that shows persistent, diffuse astro-and microgliosis along the periventricular region of the brain. 106,107 Positron emission and postmortem studies in traumatic brain injury have demonstrated activation of microglia in the thalamus several years after injury. 108,109 Persistent activation of microglia has been observed in other neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.…”

The Role of Smad Proteins for Development, Differentiation and Dedifferentiation of Neurons

“…In oligodendrocytes, it functions in a dual-mode manner by repressing the differentiation inhibitory signals of the BMP-receptor activated Smad1,5,8 activity [178] and activating oligodendrocytes-promoting factors, thus controlling proper myelination in the CNS [38].…”