title: Lenalidomide (Revlimid) administration at symptom onset is neuroprotective in a mouse model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which is currently untreatable. Inflammation plays a major role in the pathogenesis of motor neuron death in ALS. Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and Fas ligand (FasL) are amongst the most important mediators of neuro-inflammation. We have previously demonstrated that elevation of these pro-inflammatory cytokines occurs in both ALS transgenic mice and in human ALS postmortem spinal cord tissues. Lenalidomide is a potent immunomodulatory agent, with the ability to down-regulate pro-inflammatory cytokines and up-regulate anti-inflammatory cytokines. We previously reported the neuroprotective effects of lenalidomide, when treatment was started 2 months prior to onset of disease in the G93A SOD1 transgenic mouse model of ALS. Since in ALS patients, treatment can only begin after the appearance of symptoms, we sought to determine the efficacy of lenalidomide administration starting at symptom onset in the G93A SOD1 mice. We found that lenalidomide treatment extended the survival interval from the age of onset by 18.3 days ( approximately 45%). Additionally, lenalidomide treatment improved rotarod performance, reduced weight loss, and attenuated neuronal cell death in the lumbar spinal cord. Qualitative histological analysis showed that lenalidomide treatment modestly reduced the expression of the proinflammatory cytokines Fas Ligand, IL-1beta, TNF-alpha and CD40 ligand. RNA protection Assay (RPA) on a pre-selected panel of cytokines showed that proinflammatory cytokines were reduced and anti-inflammatory cytokines were up-regulated. These data encourage further clinical evaluation of lenalidomide as therapeutic strategy to block or slow disease progression in human ALS patients.
authors.affiliation: Department of Neurology, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA.
authors.forename: Arie
authors.initials: A
authors.lastname: Neymotin
authors.forename: Susanne
authors.initials: S
authors.lastname: Petri
authors.forename: Noel Y
authors.initials: NY
authors.lastname: Calingasan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wille
authors.forename: Peter
authors.initials: P
authors.lastname: Schafer
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
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Kiaei
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use; D007794:Lameness, Animal / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D000077269:Lenalidomide; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology* / Q000503:physiopathology; D015996:Survival Rate; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D016207:Cytokines; D007155:Immunologic Factors; D013792:Thalidomide; D000077269:Lenalidomide