27 research outputs found
EGFR Inhibitor Erlotinib Delays Disease Progression but Does Not Extend Survival in the SOD1 Mouse Model of ALS
<div><p></p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.</p></div
Erlotinib reduces anti-pEGFR staining in spinal cord.
<p>(A) Sample images from 6 different mice of anti-pEGFR staining in spinal cord. Top 3 images: vehicle-treated; bottom 3 images: erlotinib-treated. These images are not extreme examples from either group; they are representative of average levels of staining for each treatment group. (B) Quantification of staining using the Novus anti-pEGFR antibody in the 9-week lumbar spinal cord tissue, 24 hours post-last dose. Erlotinib significantly reduces the staining. p = 0.0124, one-tailed t test. The n/group is listed below each bar. V – vehicle; E – erlotinib.</p
Animal n per treatment group in each study.
<p>Animal n per treatment group in each study.</p
Erlotinib alleviates disease symptoms of SOD1 Tg mice.
<p>(A) Erlotinib trends toward delay in the age of onset of weight loss. This effect approaches significance, p = 0.0527 (Wilcoxon test). (B) Erlotinib delays the age of early symptom onset (p = 0.0061, Wilcoxon test). (C) Erlotinib improves the ability of mice to perform in the wire hang test, as shown by the age at which mice were last able to hang from the wire for 60s (p = 0.0479, log-rank test). The greatest difference between treatment groups is early on (∼40–110 days), suggesting a loss of efficacy of the drug as the disease becomes more severe.</p
Censoring information for survival study: animal n by cause of death/euthanasia for SOD1 Tg mice.
<p>F: female; M: male.</p>*<p>mouse was above critical weight and had normal righting reflex.</p>**<p>mouse had already shown first signs of loss of righting reflex.</p
Erlotinib improves performance of SOD1 Tg mice on the balance beam.
<p>At ∼17 weeks of age, erlotinib-treated mice performed better on balance beams of 3 different sizes than vehicle-treated littermates, both for number of foot slips (A) and for latency to traverse the beam (B). Each point is the average of 3 trials per mouse. Bars represent group mean values. V – vehicle; E – erlotinib.</p
Erlotinib does not change the amount of astroglial or microglial staining in SOD1 Tg spinal cord.
<p>(A) Percent area stained positive for GFAP in 9-week spinal cord. The n/group is listed at the bottom of each bar. (B) Example images (top: WT; bottom: Tg). (C) Percent area stained positive for Iba1 in 9-week spinal cord. The n/group is listed at the bottom of each bar. (D) Example images (top: WT; bottom: Tg). (E) Percent area stained positive for Iba1+ enlarged cells or Iba1+ cell clusters in 9-week spinal cord. The n/group is the same as in (A) and (C). (F) Example images. Top: Tg; bottom left: closer view of microglia in the dorsal horn; bottom right: green mask overlay of region in bottom left showing the area detected by the automated algorithm as positive for Iba1+ enlarged cells or Iba1+ cell clusters. V – vehicle; E – erlotinib.</p
Erlotinib does not extend lifespan of SOD1 Tg mice.
<p>Kaplan-Meier survival plot showing the lifespan of the SOD1 Tg mice treated with vehicle (blue) or erlotinib (red). The lifespan of each mouse is represented by a black dot. All mice were included in the statistical analysis. Mice that were censored in the analysis because of a non-ALS death are represented by dots that are not accompanied by a lowering of the curve.</p
Erlotinib does not preserve motor neuron synapses in SOD1 Tg mice.
<p>(A) Erlotinib did not improve loss of motor neuron innervation to the gastrocnemius muscle, examined at 9 weeks of age. As a control for the innervation score, the soleus muscle, which is a slow-twitch muscle that is resistant to disease at this age, showed no loss of innervation. The n/group is listed below each bar. (B) Example image of innervated and denervated synapses. Alpha-bungarotoxin labels the postsynaptic site of each NMJ (green, top); VChAT labels the apposing presynaptic site of the NMJ (red, middle). Bottom: merge. Arrow points to the one denervated synapse among the synapses in this field (alpha-bungarotoxin-positive synapse lacking the presynaptic marker). Scalebar 20 µm. V – vehicle; E – erlotinib.</p