title: Thalidomide and lenalidomide extend survival in a transgenic mouse model of amyotrophic lateral sclerosis.
abstract: Accumulating evidence suggests that inflammation plays a major role in the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (ALS). Important mediators of inflammation such as the cytokine tumor necrosis factor-alpha (TNF-alpha) and its superfamily member fibroblast-associated cell-surface ligand (FasL) have been implicated in apoptosis. We found increased TNF-alpha and FasL immunoreactivity in lumbar spinal cord sections of ALS patients and G93A transgenic mice. Both increased TNF-alpha and FasL immunostaining in the lumbar spinal cord of the G93A SOD1 transgenic mice occurred at 40-60 d, well before the onset of symptoms and loss of motor neurons. We tested the neuroprotective effect of thalidomide and its analog lenalidomide, pharmacological agents that inhibit the expression of TNF-alpha and other cytokines by destabilizing their mRNA. Treatment with either thalidomide or lenalidomide attenuated weight loss, enhanced motor performance, decreased motor neuron cell death, and significantly increased the life span in G93A transgenic mice. Treated G93A mice showed a reduction in TNF-alpha and FasL immunoreactivity as well as their mRNA in the lumbar spinal cord. Both compounds also reduced interleukin (IL)-12p40, IL-1alpha, and IL-1beta and increased IL-RA and TGF-beta1 mRNA. Therefore, both thalidomide and lenalidomide bear promise as therapeutic interventions for the treatment of ALS.
authors.affiliation: Department of Neurology and Neuroscience, Weill Medical College, Cornell University, New York-Presbyterian Hospital, New York, New York 10021, USA. mak2026@med.cornell.edu
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.forename: Khatuna
authors.initials: K
authors.lastname: Kipiani
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Gardian
authors.forename: Dong-Kug
authors.initials: DK
authors.lastname: Choi
authors.forename: Junyu
authors.initials: J
authors.lastname: Chen
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
authors.forename: George W
authors.initials: GW
authors.lastname: Muller
authors.forename: Charles
authors.initials: C
authors.lastname: Stewart
authors.forename: Kenneth
authors.initials: K
authors.lastname: Hensley
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D000704:Analysis of Variance; D000818:Animals; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D000077269:Lenalidomide; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics; D013534:Survival; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D016207:Cytokines; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D005904:Glial Fibrillary Acidic Protein; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D013792:Thalidomide; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000077269:Lenalidomide