The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice.
Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc-superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up-regulation of tumor necrosis factor alpha (TNFalpha) and its primary receptor TNF-RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFalpha antagonists. Walker EOC-20 microglia cells were stimulated with recombinant TNFalpha, with or without inhibitors, and the cell response was indexed by NO2- output. Three hundred and fifty-five rationally selected compounds were included in this bioassay. The arachidonic acid 5-lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non-cytotoxic antagonists tested (IC50 8 +/- 3 microm). Investigation of the G93A-SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A-SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Disease-associated gliosis and cleaved microtubule-associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFalpha antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.
West
Melinda
M
Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
Mhatre
Molina
M
Ceballos
Alex
A
Floyd
Robert A
RA
Grammas
Paula
P
Gabbita
S Prasad
SP
Hamdheydari
Ladan
L
Mai
Tammy
T
Mou
Shenyun
S
Pye
Quentin N
QN
Stewart
Charles
C
West
Stuart
S
Williamson
Kelly S
KS
Zemlan
Frank
F
Hensley
Kenneth
K
D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D015992:Body Mass Index; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020128:Inhibitory Concentration 50; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009637:Masoprocol / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology; D017628:Microglia / Q000187:drug effects* / Q000502:physiology; D008959:Models, Neurological; D009043:Motor Activity / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D010243:Paralysis / Q000188:drug therapy* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D045442:Rotarod Performance Test / Q000379:methods; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018709:Statistics, Nonparametric; D013482:Superoxide Dismutase / Q000235:genetics / Q000502:physiology; D013534:Survival / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D016859:Lipoxygenase Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins; D009569:Nitric Oxide; D009637:Masoprocol; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D003474:Curcumin