Neuropathogenesis: Processes in Neuronal Dysfunction
Session Day and Time: Wednesday 1:30 - 3:30 pm
Room: Hall B
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive paralysis for which approved treatments offer little hope. Seven (7) HIV-infected patients (pts) with an ALS-like disease responded to highly active antiretroviral therapy. ALS pts undergoing tamoxifen (TAM) therapy for breast cancer have improved, prompting TAM therapy trials in ALS pts . We investigated whether the combination of TAM and AZT synergistically delayed onset and progression of a retrovirus-induced neurodegenerative disease.
Methods: FVB/N mice were neonatally infected with Moloney murine leukemia virus ts1 mutant (http://www.neurology.wisc.edu/alscrc/tamoxifen2001/). Beginning within 4 days, TAM was injected intraperitoneally (ip), 0.5 mg/Kg daily. Littermate controls received ip saline injections. AZT (200 ug/ml) was supplied in drinking water immediately following ts1 inoculation. Scores were assigned according to established criteria for the progression of tremors and paralysis. Score 9 indicated the onset of mild paralysis, score 5, tremors and intermediate paralysis, and score 1, moribund paralysis. Statistical significance was determined by Kaplan-Meier survival analysis comparison to controls (KMSA).
Results: Control mice experienced onset of disease (score 9) at median age 30 days, and the moribund condition (score 1) at 41 days. Mice treated with TAM alone reached score 9 at 35 days and score 1 at 61 days (p = 0.0000, n = 35, KMSA). Mice treated with AZT alone reached score 9 at 34 days and score 1 at 52 days (p = 0.0002 and 0.0005, respectively, n = 14, KMSA). Mice receiving AZT and TAM in combination reached score 9 at 54 days and score 1 at 80 days (p = 0.0000, n = 13, KMSA).
Conclusions: Compared to saline-injected controls: 1) treatment with TAM alone and AZT alone delayed onset of retrovirus-induced neurodegeneration by 5 and 4 days, respectively; and 2) combination therapy delayed disease onset by 24 days indicating a synergistic effect. However, mice receiving combination therapy reached score 1 at 80 days, a 26 days duration of symptoms from onset at 54 days. This duration equaled the duration of symptoms (from 35 to 61 days) in mice treated with TAM alone. In contrast, AZT therapy alone resulted in 18 days duration of symptoms (from 34 to 52 days). These results suggest a possible benefit of TAM therapy in combination with antiviral therapy to delay onset and progression of neurological symptoms in HIV pts.