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Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.

Trias E, Ibarburu S, Barreto-Núñez R, Babdor J, Maciel TT, Guillo M, Gros L, Dubreuil P, Díaz-Amarilla P, Cassina P, Martínez-Palma L, Moura IC, Beckman JS, Hermine O, Barbeito L - J Neuroinflammation (2016)

Bottom Line: Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown.We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations.Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.

ABSTRACT

Background: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.

Methods: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.

Results: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.

Conclusions: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.

No MeSH data available.


Related in: MedlinePlus

Masitinib treatment after paralysis onset increased survival of SOD1G93A transgenic rats. a Kaplan-Meier survival curves from masitinib-treated and vehicle-treated SOD1G93A rats. SOD1 G93A transgenic rats were treated with masitinib (30 mg/kg/day) or vehicle (water, n = 29, blue line) immediately after observation of paralysis onset of one limb (day 1; n = 14, red line) or starting 7 days after paralysis onset (day 7, n = 9, green line). There was a statistically significant difference in the probability of survival for both masitinib-treated groups when compared with vehicle-treated group, according to the log-rank test of the Kaplan-Meier analysis (p < 0.0006 for masitinib—gait onset vs. vehicle and p < 0.00025 for masitinib—7 days onset vs. vehicle). b The graph shows the mean survival of the three different groups. All data are expressed as mean ± SEM. p < 0.01 was considered significant
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Fig5: Masitinib treatment after paralysis onset increased survival of SOD1G93A transgenic rats. a Kaplan-Meier survival curves from masitinib-treated and vehicle-treated SOD1G93A rats. SOD1 G93A transgenic rats were treated with masitinib (30 mg/kg/day) or vehicle (water, n = 29, blue line) immediately after observation of paralysis onset of one limb (day 1; n = 14, red line) or starting 7 days after paralysis onset (day 7, n = 9, green line). There was a statistically significant difference in the probability of survival for both masitinib-treated groups when compared with vehicle-treated group, according to the log-rank test of the Kaplan-Meier analysis (p < 0.0006 for masitinib—gait onset vs. vehicle and p < 0.00025 for masitinib—7 days onset vs. vehicle). b The graph shows the mean survival of the three different groups. All data are expressed as mean ± SEM. p < 0.01 was considered significant

Mentions: We then explored whether chronic treatment with masitinib could reduce the number of aberrant glial cells in the degenerating spinal cord, which were identifiable as large GFAP/S100β-positive cells located around motor neurons as described previously [4]. Rats were orally treated with masitinib (30 mg/kg/day), starting right after paralysis onset and during the next 20 days, corresponding to the average post-paralysis survival in untreated rats (Fig. 5). Only rats that initiated paralysis in the hind limbs were used in the experiments in order to reduce experimental variables. As compared with rats treated with vehicle, masitinib significantly reduced the number of aberrant glial cells in the lumbar spinal cord by 40 % (Fig. 3a).Fig. 3


Post-paralysis tyrosine kinase inhibition with masitinib abrogates neuroinflammation and slows disease progression in inherited amyotrophic lateral sclerosis.

Trias E, Ibarburu S, Barreto-Núñez R, Babdor J, Maciel TT, Guillo M, Gros L, Dubreuil P, Díaz-Amarilla P, Cassina P, Martínez-Palma L, Moura IC, Beckman JS, Hermine O, Barbeito L - J Neuroinflammation (2016)

Masitinib treatment after paralysis onset increased survival of SOD1G93A transgenic rats. a Kaplan-Meier survival curves from masitinib-treated and vehicle-treated SOD1G93A rats. SOD1 G93A transgenic rats were treated with masitinib (30 mg/kg/day) or vehicle (water, n = 29, blue line) immediately after observation of paralysis onset of one limb (day 1; n = 14, red line) or starting 7 days after paralysis onset (day 7, n = 9, green line). There was a statistically significant difference in the probability of survival for both masitinib-treated groups when compared with vehicle-treated group, according to the log-rank test of the Kaplan-Meier analysis (p < 0.0006 for masitinib—gait onset vs. vehicle and p < 0.00025 for masitinib—7 days onset vs. vehicle). b The graph shows the mean survival of the three different groups. All data are expressed as mean ± SEM. p < 0.01 was considered significant
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4940876&req=5

Fig5: Masitinib treatment after paralysis onset increased survival of SOD1G93A transgenic rats. a Kaplan-Meier survival curves from masitinib-treated and vehicle-treated SOD1G93A rats. SOD1 G93A transgenic rats were treated with masitinib (30 mg/kg/day) or vehicle (water, n = 29, blue line) immediately after observation of paralysis onset of one limb (day 1; n = 14, red line) or starting 7 days after paralysis onset (day 7, n = 9, green line). There was a statistically significant difference in the probability of survival for both masitinib-treated groups when compared with vehicle-treated group, according to the log-rank test of the Kaplan-Meier analysis (p < 0.0006 for masitinib—gait onset vs. vehicle and p < 0.00025 for masitinib—7 days onset vs. vehicle). b The graph shows the mean survival of the three different groups. All data are expressed as mean ± SEM. p < 0.01 was considered significant
Mentions: We then explored whether chronic treatment with masitinib could reduce the number of aberrant glial cells in the degenerating spinal cord, which were identifiable as large GFAP/S100β-positive cells located around motor neurons as described previously [4]. Rats were orally treated with masitinib (30 mg/kg/day), starting right after paralysis onset and during the next 20 days, corresponding to the average post-paralysis survival in untreated rats (Fig. 5). Only rats that initiated paralysis in the hind limbs were used in the experiments in order to reduce experimental variables. As compared with rats treated with vehicle, masitinib significantly reduced the number of aberrant glial cells in the lumbar spinal cord by 40 % (Fig. 3a).Fig. 3

Bottom Line: Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown.We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations.Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.

View Article: PubMed Central - PubMed

Affiliation: Institut Pasteur de Montevideo, Mataojo 2020, Montevideo, 11.400, Uruguay.

ABSTRACT

Background: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS.

Methods: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset.

Results: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %.

Conclusions: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.

No MeSH data available.


Related in: MedlinePlus