Neuroprotective agents for clinical trials in ALS: A systematic assessment
William JBurke, Saint Louis University, 3635 Vista at Grand; St. Louis, MOburkewj@slu.edu
Submitted September 20, 2006
In their article on neuroprotective agents for ALS, Traynor et al [1] list 24 potential neuroprotective drugs for patients with ALS. Taxol is not mentioned. However, two cell death mechanisms postulated to underlie neuronal death in ALS, defective axonal transport [2] and calcium-mediated toxicity [3] are reversed by taxol in vitro [4] and in vivo. [5]
In vitro at an optimum concentration, taxol blocks the toxicity of the calcium ionophore A23187. [4] Similarly glutamate, thru activation of ionotropic receptors, allows calcium influx into neurons and potentiates toxicity of mutant superoxide dismutase in motor neurons by a calcium dependent mechanism. [6]
Riluzole, the only effective treatment for ALS, blocks glutamate release and thus could be inhibiting this calcium mediated cell death mechanism. The two cell death mechanisms may not be entirely independent because calcium inhibits the formation of the microtubule transport system. In a transgenic (Tg) mouse model of degeneration of spinal motor neurons, Zhang et al. show that taxol improves fast axonal transport, protects against axonal degeneration of spinal motor neurons and improves mobility in Tg mice treated with taxol compared to controls. [5]
There are two potential problems with use of taxol. It produces a painful mainly sensory neuropathy in 50% to 60% of patients taking it for various forms of cancer. Brain concentrations are very low after intravenous injection. However both of these problems have potential solutions. First, there are symptomatic and potentially protective treatments for taxol-induced sensory neuropathy. [7] Secondly, chemical modifications of taxol decrease its affinity for the multidrug resistance protein, P-glycoprotein, and enhance taxol permeation across the blood brain barrier. [8] These modifications should make taxol more effective in clinical trials if it shows promise in in vitro and in vivo models of ALS.
Taxol is currently being evaluated in animal models as a potential therapy for Alzheimer’s disease. [5] It deserves consideration for trials in in vitro and in vivo models of ALS.
References
1. Traynor BJ, Bruijn L, Conwit R, et al. Neuroprotective agents for clinical trials in ALS. Neurology 2006; 67:20-27.
2. Collard JF, Cote F, Julien JP. Defective axonal transport in a
transgenic mouse model of amyotrophic lateral sclerosis. Nature 1995; 375: 12-13.
3. Alexianu ME, Ho B-K, Mohamed AH, La Bella V, Smith RG, Appel SH. The role of calcium-binding proteins in selective motor neuron vulnerability in ALS. Annals of Neurology 1994; 36: 846-858.
4. Burke WJ, Raghu G, Strong R. Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells. Life Sciences 1994; 55: 313-319.
5.Zhang B, Maiti A, Shively S, et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci 2005; 102: 227-231.
6. Roy J, Minotti S, Dong L, Figlewicz DA, Durham HD. Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms. J Neurosci 1998; 18:9673-9684.
7. Wang MS, Davis AA, Culver DG, Wang Q, Powers JC, Glass JD. Calpain inhibition protects against Taxol-induced sensory neuropathy. Brain 2004;
127: 671-679.
8. Rice A, Liu Y, Michaelis ML, Himes RH, Georg GI, Audus KL.
Chemical modification of placitaxel (Taxol) reduces P-glycoprotein
interaction and increases permeation across the blood-brain barrier in
vitro and in situ. J Med Chem 2005; 48(3): 832-838.
Disclosure: The author reports no conflicts of interest.
In their article on neuroprotective agents for ALS, Traynor et al [1] list 24 potential neuroprotective drugs for patients with ALS. Taxol is not mentioned. However, two cell death mechanisms postulated to underlie neuronal death in ALS, defective axonal transport [2] and calcium-mediated toxicity [3] are reversed by taxol in vitro [4] and in vivo. [5]
In vitro at an optimum concentration, taxol blocks the toxicity of the calcium ionophore A23187. [4] Similarly glutamate, thru activation of ionotropic receptors, allows calcium influx into neurons and potentiates toxicity of mutant superoxide dismutase in motor neurons by a calcium dependent mechanism. [6]
Riluzole, the only effective treatment for ALS, blocks glutamate release and thus could be inhibiting this calcium mediated cell death mechanism. The two cell death mechanisms may not be entirely independent because calcium inhibits the formation of the microtubule transport system. In a transgenic (Tg) mouse model of degeneration of spinal motor neurons, Zhang et al. show that taxol improves fast axonal transport, protects against axonal degeneration of spinal motor neurons and improves mobility in Tg mice treated with taxol compared to controls. [5]
There are two potential problems with use of taxol. It produces a painful mainly sensory neuropathy in 50% to 60% of patients taking it for various forms of cancer. Brain concentrations are very low after intravenous injection. However both of these problems have potential solutions. First, there are symptomatic and potentially protective treatments for taxol-induced sensory neuropathy. [7] Secondly, chemical modifications of taxol decrease its affinity for the multidrug resistance protein, P-glycoprotein, and enhance taxol permeation across the blood brain barrier. [8] These modifications should make taxol more effective in clinical trials if it shows promise in in vitro and in vivo models of ALS.
Taxol is currently being evaluated in animal models as a potential therapy for Alzheimer’s disease. [5] It deserves consideration for trials in in vitro and in vivo models of ALS.
References
1. Traynor BJ, Bruijn L, Conwit R, et al. Neuroprotective agents for clinical trials in ALS. Neurology 2006; 67:20-27.
2. Collard JF, Cote F, Julien JP. Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature 1995; 375: 12-13.
3. Alexianu ME, Ho B-K, Mohamed AH, La Bella V, Smith RG, Appel SH. The role of calcium-binding proteins in selective motor neuron vulnerability in ALS. Annals of Neurology 1994; 36: 846-858.
4. Burke WJ, Raghu G, Strong R. Taxol protects against calcium-mediated death of differentiated rat pheochromocytoma cells. Life Sciences 1994; 55: 313-319.
5.Zhang B, Maiti A, Shively S, et al. Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model. Proc Natl Acad Sci 2005; 102: 227-231.
6. Roy J, Minotti S, Dong L, Figlewicz DA, Durham HD. Glutamate potentiates the toxicity of mutant Cu/Zn-superoxide dismutase in motor neurons by postsynaptic calcium-dependent mechanisms. J Neurosci 1998; 18:9673-9684.
7. Wang MS, Davis AA, Culver DG, Wang Q, Powers JC, Glass JD. Calpain inhibition protects against Taxol-induced sensory neuropathy. Brain 2004; 127: 671-679.
8. Rice A, Liu Y, Michaelis ML, Himes RH, Georg GI, Audus KL. Chemical modification of placitaxel (Taxol) reduces P-glycoprotein interaction and increases permeation across the blood-brain barrier in vitro and in situ. J Med Chem 2005; 48(3): 832-838.
Disclosure: The author reports no conflicts of interest.