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Overview

Background —Neuregulins are a family of peptide growth factors that promote cell growth and viability. The potential role of neuregulin-erbB signaling in hypertrophic growth and later failure in the adult heart in vivo is not known. Methods and Results —We used ribonuclease protection assays to quantify mRNA levels of neuregulin, erbB2, and erbB4 in left ventricular (LV) tissue and myocytes of normal rats and rats with aortic stenosis with pressure-overload hypertrophy 6 and 22 weeks after banding. At both stages of hypertrophy, Northern blot analyses of mRNA from LV myocytes showed upregulation of atrial natriuretic peptide, a molecular marker of hypertrophy ( P <0.05). LV tissue neuregulin message levels were similar in animals with aortic stenosis compared with controls ( P =NS) and were not detectable in myocytes. LV erbB2 and erbB4 message levels in LV tissue and myocytes were maintained during early compensatory hypertrophy in 6-week aortic stenosis animals compared with age-matched controls; in contrast, erbB2 and erbB4 message levels were depressed in 22-week aortic stenosis animals at the stage of early failure (both P <0.01 vs age-matched controls). Immunoblotting of erbB2 and erbB4 also showed normal protein levels in 6-week aortic stenosis animals compared with controls; however, erbB2 and erbB4 protein levels were depressed in 22-week aortic stenosis animals (48% decrease in erbB2, P <0.05, and 43% decrease in erbB4, P <0.01) relative to age-matched controls. Conclusions —The neuregulin receptors erbB2 and erbB4 are downregulated at both the message and protein levels at the stage of early failure in animals with chronic hypertrophy secondary to aortic stenosis. These data suggest a role for disabled erbB receptor signaling in the transition from compensatory hypertrophy to failure.

01 Jan 1999·Advances in Experimental Medicine and Biology

Neuregulin in Neuron/Glial Interactions in the Central Nervous System

Author: Elizebeth Happel ; Florence Noel ; Mark A. Marchionni ; Yan Ling Gao ; Deborah Lawson ; Cedric S. Raine ; Philip Tofilon ; Renee Garcia-Arenas ; Barbara Cannella ; Carolyn Hoban ; David Gwynne

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). This study has focused on recombinant human GGF2 (rhGGF2) and it’s potential to affect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis (MS). Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases, and GGF2 treatment led to delayed signs, decreased severity and resulted in statistically significant reductions in relapse rate. Further, rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased expression of myelin basic protein exon 2, a marker for remyelination, and with an increase of the regulatory cytokine, IL-10. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated upon the clinical, pathologic and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a Th2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of MS (Cannella et al., 1998).

01 Jan 1999·Advances in experimental medicine and biology

Neuregulin in neuron/glial interactions in the central nervous system. GGF2 diminishes autoimmune demyelination, promotes oligodendrocyte progenitor expansion, and enhances remyelination.

Article

Author: Garcia-Arenas, R ; Gao, Y L ; Lawson, D ; Tofilon, P ; Noel, F ; Hoban, C ; Happel, E ; Marchionni, M A ; Gwynne, D ; Cannella, B ; Raine, C S

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). This study has focused on recombinant human GGF2 (rhGGF2) and it's potential to affect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis (MS). Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases, and GGF2 treatment led to delayed signs, decreased severity and resulted in statistically significant reductions in relapse rate. Further, rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased expression of myelin basic protein exon 2, a marker for remyelination, and with an increase of the regulatory cytokine, IL-10. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated upon the clinical, pathologic and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a Th2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of MS (Cannella et al., 1998).

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Pipeline Snapshot as of 21 Dec 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

CNS-5788 ( NMDA receptor )	Stroke More	Pending
CNS-5151 ( Sodium channels )	Stroke More	Pending
CNS-5065 ( NMDA receptor )	Neurodegenerative Diseases More	Pending
CNS-2103 ( calcium channel )	Neurodegenerative Diseases More	Pending
CNS-1145	Stroke More	Pending