Contributions
Abstract: P582
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Objective: Determine if melanocortin receptor (MCR) and sigma-1 receptor (s-1R) agonists protect oligodendrocytes (OL) from cytotoxic factors released by B cells from patients with multiple sclerosis (MS).
Background: No disease modifying therapy for relapsing MS has been shown to directly protect OL/myelin. OL express MCRs in vitro that mediate the ability of adrenal cortical stimulating hormone (ACTH 1-39), a melanocortin, to protect OL and OL precursors (OPC) from mechanisms likely important in MS: excitotoxicity, reactive oxygen species, inflammation and apoptosis. Dextromethorphan (DM) and Anavex®2-73, s-1R agonists and weak NMDAR antagonists, protect OL and OPC from these same toxic stimuli. B cells from blood of MS patients, but not normals, release toxic factors/s that kill OL in vitro involving apoptosis. We sought to determine if ACTH, DM and Anavex2®-73 also inhibit OL death induced by products of MS B cells.
Methods: B cells were isolated by positive selection with anti-CD19 MACS beads. B cells were cultured without any in vitro stimulation, supernatants (Sup) harvested and frozen until testing. Glial cell cultures prepared from brains of neonatal rats contained OL, OPC, astrocytes and microglia. ACTH, DM, Anavex®2-73 or additional medium was added to glial cultures prior to adding B cell Sup. OL death was determined by trypan blue uptake.
Results: Sup from MS B cells were toxic to OL, those from normals were not. ACTH, DM and Anavex®2-73 all markedly inhibit OL death induced by MS B cell Sup. Antagonists of MCR or s-1R added prior to Anavex®2-73 reverse the ability to block B cell Sup mediated cytotoxicity.
Conclusions: ACTH, DM and Anavex®2-73 are able to inhibit B cell Sup mediated death of OL in vitro. Since there is progression and degeneration in many treated MS patients, development of agonists for MCR and s-1R are potential protective treatments for patients with MS.
Disclosure: Funding: National Multiple Sclerosis Society (RL, JB, AB-O), Research Foundation of the MS Society of Canada, Parker Webber Chair of Neurology Endowment (DMC Foundation/Wayne State University)., NIH and Melissa and Paul Anderson Chair in Neuroinflammatioin (Univeristy of Pennsylvania) RL has received funding for research from Mallinckrodt, Novartis, Teva, Sanofi-Genzyme, Genentech/Roche, Medimmune and Alexion; has consulted for Alexion, Celegene, Syntimmune, GLG Consulting, Insights Consulting and Alpha Sites Consulting and served as a speaker for non-branded talks for Teva. LN has nothing to declare. HT has nothing to declare. AB-O has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Atara Biotherapeutics, Biogen Idec, Celgene,/Receptos, Genentech/Roche, GlaxoSmith Kline, MAPI, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme. JB has nothing to declare.
Abstract: P582
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Objective: Determine if melanocortin receptor (MCR) and sigma-1 receptor (s-1R) agonists protect oligodendrocytes (OL) from cytotoxic factors released by B cells from patients with multiple sclerosis (MS).
Background: No disease modifying therapy for relapsing MS has been shown to directly protect OL/myelin. OL express MCRs in vitro that mediate the ability of adrenal cortical stimulating hormone (ACTH 1-39), a melanocortin, to protect OL and OL precursors (OPC) from mechanisms likely important in MS: excitotoxicity, reactive oxygen species, inflammation and apoptosis. Dextromethorphan (DM) and Anavex®2-73, s-1R agonists and weak NMDAR antagonists, protect OL and OPC from these same toxic stimuli. B cells from blood of MS patients, but not normals, release toxic factors/s that kill OL in vitro involving apoptosis. We sought to determine if ACTH, DM and Anavex2®-73 also inhibit OL death induced by products of MS B cells.
Methods: B cells were isolated by positive selection with anti-CD19 MACS beads. B cells were cultured without any in vitro stimulation, supernatants (Sup) harvested and frozen until testing. Glial cell cultures prepared from brains of neonatal rats contained OL, OPC, astrocytes and microglia. ACTH, DM, Anavex®2-73 or additional medium was added to glial cultures prior to adding B cell Sup. OL death was determined by trypan blue uptake.
Results: Sup from MS B cells were toxic to OL, those from normals were not. ACTH, DM and Anavex®2-73 all markedly inhibit OL death induced by MS B cell Sup. Antagonists of MCR or s-1R added prior to Anavex®2-73 reverse the ability to block B cell Sup mediated cytotoxicity.
Conclusions: ACTH, DM and Anavex®2-73 are able to inhibit B cell Sup mediated death of OL in vitro. Since there is progression and degeneration in many treated MS patients, development of agonists for MCR and s-1R are potential protective treatments for patients with MS.
Disclosure: Funding: National Multiple Sclerosis Society (RL, JB, AB-O), Research Foundation of the MS Society of Canada, Parker Webber Chair of Neurology Endowment (DMC Foundation/Wayne State University)., NIH and Melissa and Paul Anderson Chair in Neuroinflammatioin (Univeristy of Pennsylvania) RL has received funding for research from Mallinckrodt, Novartis, Teva, Sanofi-Genzyme, Genentech/Roche, Medimmune and Alexion; has consulted for Alexion, Celegene, Syntimmune, GLG Consulting, Insights Consulting and Alpha Sites Consulting and served as a speaker for non-branded talks for Teva. LN has nothing to declare. HT has nothing to declare. AB-O has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from: Atara Biotherapeutics, Biogen Idec, Celgene,/Receptos, Genentech/Roche, GlaxoSmith Kline, MAPI, Medimmune, Merck/EMD Serono, Novartis, Sanofi-Genzyme. JB has nothing to declare.