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Recent advances in amyotrophic lateral sclerosis research: perspectives for personalized clinical application.

Benkler C, Offen D, Melamed E, Kupershmidt L, Amit T, Mandel S, Youdim MB, Weinreb O - EPMA J (2010)

Bottom Line: Currently, over 150 different potential therapeutic agents or strategies have been tested in preclinical models of ALS.Unfortunately, therapeutic modifiers of murine ALS have failed to be successfully translated into strategies for patients, probably because of differences in pharmacokinetics of the therapeutic agents, route of delivery, inefficiency of the agents to affect the distinct pathologies of the disease or inherent limitations of the available animal models.Additionally, a better management of ALS therapy should include understanding the interactions between potential risk factors, biomarkers and heterogeneous clinical features of the patients, aiming to manage their adverse events or personalize the safety profile of these agents.

View Article: PubMed Central - PubMed

Affiliation: Felsenstein Medical Research Center, Tel Aviv University, Tel-Aviv, Israel.

ABSTRACT
Treatment of amyotrophic lateral sclerosis (ALS) has been fueled, in part, by frustration over the shortcomings of the symptomatic drugs available, since these do not impede the progression of this disease. Currently, over 150 different potential therapeutic agents or strategies have been tested in preclinical models of ALS. Unfortunately, therapeutic modifiers of murine ALS have failed to be successfully translated into strategies for patients, probably because of differences in pharmacokinetics of the therapeutic agents, route of delivery, inefficiency of the agents to affect the distinct pathologies of the disease or inherent limitations of the available animal models. Given the multiplicity of the pathological mechanisms implicated in ALS, new therapies should consider the simultaneous manipulation of multiple targets. Additionally, a better management of ALS therapy should include understanding the interactions between potential risk factors, biomarkers and heterogeneous clinical features of the patients, aiming to manage their adverse events or personalize the safety profile of these agents. This review will discuss novel pharmacological approaches concerning adjusted therapy for ALS patients: iron-binding brain permeable multimodal compounds, genetic manipulation and cell-based treatment.

No MeSH data available.


Related in: MedlinePlus

Attenuation of the neuritogenic effect of M30 and HLA20 by specific inhibitors of PKC and MAPK/ERK kinase (MEK). NSC-34 cells were incubated with PKC inhibitor GF109203X (2.5 µM) or MEK inhibitor PD98059 (10 µM) for 1 h before administration of M30 (10 µM) or HLA20 (10 µM) for a further 24 h. The cells were fixed and permeabilized for GAP-43 detection. a The images are representative fields from three independent experiments. b the histogram represents averages of the differentiated cell percentages (± SEM). One-way ANOVA followed by Student’s t-test was used for statistic analysis. * p < 0.001 vs. respective controls; # p < 0.001 vs. M30 and HLA20 only (without inhibitors) treated cells. (Reproduced from [36])
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Fig3: Attenuation of the neuritogenic effect of M30 and HLA20 by specific inhibitors of PKC and MAPK/ERK kinase (MEK). NSC-34 cells were incubated with PKC inhibitor GF109203X (2.5 µM) or MEK inhibitor PD98059 (10 µM) for 1 h before administration of M30 (10 µM) or HLA20 (10 µM) for a further 24 h. The cells were fixed and permeabilized for GAP-43 detection. a The images are representative fields from three independent experiments. b the histogram represents averages of the differentiated cell percentages (± SEM). One-way ANOVA followed by Student’s t-test was used for statistic analysis. * p < 0.001 vs. respective controls; # p < 0.001 vs. M30 and HLA20 only (without inhibitors) treated cells. (Reproduced from [36])

Mentions: Another important characteristic aspect of M30 and HLA20 is their ability to induce differentiation, cell elongation and stimulate neurite outgrowth of NSC-34 motoneuron cells [36]. These morphological modifications were accompanied by an increase in the immunoreactivity of the neuronal marker Growth-associated protein, GAP-43, and decrease in cyclin D1 expression [36], in accordance with results of previous studies, demonstrating that M30 induced a neuritogenic effect and triggered cell cycle arrest in G0/G1 in rat pheochromocytoma PC12 and human SH-SY5Y neuroblastoma cell lines [33]. Indeed, many cell cycle regulating factors require iron for their function [61, 62]. Thus, an inhibitory effect of the novel iron-chelator compounds on cell cycle reentry [33], may trigger the process of differentiation through various iron-associated biological events [63]. In addition, the effect of the multifunctional drugs on motoneuron differentiation may be associated with their propargyl moiety, since N-propargylamine and rasagiline were shown to up-regulate BDNF and glial cell line-derived neurotrophic factor (GDNF) gene expression in PC12 cells [43, 45]. In in vitro studies in NSC-34 cell, M30 and HLA20 were demonstrated to induce mRNA levels of BDNF, which is a well recognized neurotrophic factor for motoneurons [36, 64–66]. Motor neuron differentiation, induced by M30 and HLA20, was shown to be modulated by inhibitors of ERK/MAPK and PKC signaling pathways (Fig. 3) [36]. In results, complementary to inhibition studies, we found that the drugs significantly increased the immunoreactivity of phosphorylated MAPK and PKC in NSC-34 cells, further indicating the involvement of both ERK and PKC activation [36].Fig. 3


Recent advances in amyotrophic lateral sclerosis research: perspectives for personalized clinical application.

Benkler C, Offen D, Melamed E, Kupershmidt L, Amit T, Mandel S, Youdim MB, Weinreb O - EPMA J (2010)

Attenuation of the neuritogenic effect of M30 and HLA20 by specific inhibitors of PKC and MAPK/ERK kinase (MEK). NSC-34 cells were incubated with PKC inhibitor GF109203X (2.5 µM) or MEK inhibitor PD98059 (10 µM) for 1 h before administration of M30 (10 µM) or HLA20 (10 µM) for a further 24 h. The cells were fixed and permeabilized for GAP-43 detection. a The images are representative fields from three independent experiments. b the histogram represents averages of the differentiated cell percentages (± SEM). One-way ANOVA followed by Student’s t-test was used for statistic analysis. * p < 0.001 vs. respective controls; # p < 0.001 vs. M30 and HLA20 only (without inhibitors) treated cells. (Reproduced from [36])
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3405320&req=5

Fig3: Attenuation of the neuritogenic effect of M30 and HLA20 by specific inhibitors of PKC and MAPK/ERK kinase (MEK). NSC-34 cells were incubated with PKC inhibitor GF109203X (2.5 µM) or MEK inhibitor PD98059 (10 µM) for 1 h before administration of M30 (10 µM) or HLA20 (10 µM) for a further 24 h. The cells were fixed and permeabilized for GAP-43 detection. a The images are representative fields from three independent experiments. b the histogram represents averages of the differentiated cell percentages (± SEM). One-way ANOVA followed by Student’s t-test was used for statistic analysis. * p < 0.001 vs. respective controls; # p < 0.001 vs. M30 and HLA20 only (without inhibitors) treated cells. (Reproduced from [36])
Mentions: Another important characteristic aspect of M30 and HLA20 is their ability to induce differentiation, cell elongation and stimulate neurite outgrowth of NSC-34 motoneuron cells [36]. These morphological modifications were accompanied by an increase in the immunoreactivity of the neuronal marker Growth-associated protein, GAP-43, and decrease in cyclin D1 expression [36], in accordance with results of previous studies, demonstrating that M30 induced a neuritogenic effect and triggered cell cycle arrest in G0/G1 in rat pheochromocytoma PC12 and human SH-SY5Y neuroblastoma cell lines [33]. Indeed, many cell cycle regulating factors require iron for their function [61, 62]. Thus, an inhibitory effect of the novel iron-chelator compounds on cell cycle reentry [33], may trigger the process of differentiation through various iron-associated biological events [63]. In addition, the effect of the multifunctional drugs on motoneuron differentiation may be associated with their propargyl moiety, since N-propargylamine and rasagiline were shown to up-regulate BDNF and glial cell line-derived neurotrophic factor (GDNF) gene expression in PC12 cells [43, 45]. In in vitro studies in NSC-34 cell, M30 and HLA20 were demonstrated to induce mRNA levels of BDNF, which is a well recognized neurotrophic factor for motoneurons [36, 64–66]. Motor neuron differentiation, induced by M30 and HLA20, was shown to be modulated by inhibitors of ERK/MAPK and PKC signaling pathways (Fig. 3) [36]. In results, complementary to inhibition studies, we found that the drugs significantly increased the immunoreactivity of phosphorylated MAPK and PKC in NSC-34 cells, further indicating the involvement of both ERK and PKC activation [36].Fig. 3

Bottom Line: Currently, over 150 different potential therapeutic agents or strategies have been tested in preclinical models of ALS.Unfortunately, therapeutic modifiers of murine ALS have failed to be successfully translated into strategies for patients, probably because of differences in pharmacokinetics of the therapeutic agents, route of delivery, inefficiency of the agents to affect the distinct pathologies of the disease or inherent limitations of the available animal models.Additionally, a better management of ALS therapy should include understanding the interactions between potential risk factors, biomarkers and heterogeneous clinical features of the patients, aiming to manage their adverse events or personalize the safety profile of these agents.

View Article: PubMed Central - PubMed

Affiliation: Felsenstein Medical Research Center, Tel Aviv University, Tel-Aviv, Israel.

ABSTRACT
Treatment of amyotrophic lateral sclerosis (ALS) has been fueled, in part, by frustration over the shortcomings of the symptomatic drugs available, since these do not impede the progression of this disease. Currently, over 150 different potential therapeutic agents or strategies have been tested in preclinical models of ALS. Unfortunately, therapeutic modifiers of murine ALS have failed to be successfully translated into strategies for patients, probably because of differences in pharmacokinetics of the therapeutic agents, route of delivery, inefficiency of the agents to affect the distinct pathologies of the disease or inherent limitations of the available animal models. Given the multiplicity of the pathological mechanisms implicated in ALS, new therapies should consider the simultaneous manipulation of multiple targets. Additionally, a better management of ALS therapy should include understanding the interactions between potential risk factors, biomarkers and heterogeneous clinical features of the patients, aiming to manage their adverse events or personalize the safety profile of these agents. This review will discuss novel pharmacological approaches concerning adjusted therapy for ALS patients: iron-binding brain permeable multimodal compounds, genetic manipulation and cell-based treatment.

No MeSH data available.


Related in: MedlinePlus