Invited Symposium: Oxidative Stress and the CNS
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Clinical pathophysiological insights
Amyotrophic lateral sclerosis (ALS) was described more than a century ago in Paris by J.M. Charcot . Even now this severe neurological disorder has still the same prognosis and no cure was discovered although recent findings have brought new hopes in ALS therapy (1,2). The disease is clinically characterized by a progressive muscle weakness and amyotrophy starting in limbs or affecting muscles with a bulbar innervation. Fasciculations and respiratory failure are accompanied by clinical signs of corticospinal tract deficit marled by spasticity and frisk tendon reflexes. Neuropathological features are the loss of upper motoneurons in the motor cortex and lower motoneurons in the brain stern and the spinal cord.
Neurogenic muscular atrophy is also a striking feature. The pathophysiology of ALS is unknown although recently mutations of the superoxide dismutase 1 gene were discovered in a subject of familial ALS (3). This has strengthened the idea that free-radicals could be involved in this disease. In recent years a growing body of evidence has suggested that glutamate toxicity called excitotoxicity could also be involved in the pathogenesis of motoneuron degeneration. In the recent years, the relations between excitotoxicity and oxidative stress were discovered suggesting that these combined mechanisms of neuronal death could both contribute to neuronal loss detected in several neurological disorders.
ALS and excitotoxicity
Glutamate is one of the major excitatory neurotransmitter in the central nervous system but also a potent neurotoxin when post synaptic receptors are overstimulated or in case of neuron energy deficit. Excitotoxicity was implicated in a large variety of neurological disorder (4) including motoneuron diseases. Lathyrism is marked by the sudden or more progressive onset of spastic paraplegia in patients who heavily consumed the Lathyrus sativus. Lathyrus sativus contains a potent excitotoxin BOAA that is responsible for neuronal death in experimental conditions (6). Abnormal glutamate metabolism was found in patients with ALS including increased levels of glutamate in serum and decreased glutamate dehydrogenase activity in peripheral lymphocytes (7,8).
The glutamate re-uptake was found diminished in motor cortex and spinal cords of ALS patients (9) and the glial glutamate transporter protein GLT-1 is reduced in affected brain regions (10). Further studies revealed that an aberrant mRNA processing could be at the origin of these anomalies (11). Another factor contributing to the excitotoxic hypothesis is the discovery that ALS CSF contains neurotoxic factors whose cellular actions are mediated by post synaptic AMPA/kainate glutamate receptors (12). Motoneurons also seem to express less calcium buffering proteins able to reduce the deleterious effect of increased intracellular calcium concentration following excitotoxicity (13). All these findings led to propose anti-glutamate therapy in ALS. Riluzole, an agent reducing the glutamate release from pre-synaptic terminal, was the only drug able to mildly alter the evolution of the disease and was recently approved (14).
ALS and oxidative stress
The relation between ALS and oxidative stress has gained increasing acceptance since the discovery in a subgroup of familial ALS patients, with mutation in the SOD1 gene. This subgroup represents only 20 % of all familial cases but this was the first time that gene mutations were involved in ALS. This finding was reinforced some years later by the discovery that transgenic mice overexpressing human mutated SOD1 gene developed a motor deficit with motoneuron degeneration (15). Several authors suggested that in these animals these mutated proteins could produce a gain of function. Recently, several reports have noted the overproduction of free radicals in these mice (16,17). But more recently, a study modifying the level of wild type SOD in these SOD1 transgenic mice did not find any effect on the mutant-mediated disease raising the question of whether toxicity comes from superoxide-mediated stress (18).
Mitochondrial dysfunction was also involved in the pathophysiology of neurodegenerative disorders (19). These dysfunctions induce several cellular toxic effects including generation of free-radicals, abnormal calcium metabolism and activation of the permeability transition of mitochondria. This pattern of events can result in an excessive sensitivity of neurons to extracellular glutamate, producing excitotoxicity. It is interesting to notice that the presence of cytoplasmic calbindin D28K, a calcium buffering protein, give a greater resistance to oxidative stress (20) and that antioxidant drugs protect neurons from ALS CSF toxicity in vitro (21). The combination of excitotoxicity and free radicals toxicity could be at the origin of a selective motoneuron death in ALS.
Excitotoxicity and oxidative stress
During the last years, reports have focused on the relations between excitotoxicity and the induction of oxidant stress. It was shown that NMDA toxicity produces superoxide ions (22) and that oxygen free radicals can block glutamate uptake by astrocytes (23). There are evidences showing that abnormal oxidative damage to post mortem proteins are detected in brain and spinal cord of ALS patients (24,25). It is thus possible to hypothesize that both excitotoxicity and oxidative stress can trigger cellular functions leading to motoneuron death.
Experimentally, intrathecal injection of kainic acid is responsible for motoneuron death (26) and experimentally induced oxidative stress can kill motoneurons in the rat spinal cord (27). Motoneurons are also more sensitive to calcium mediated AMPA/kainate toxicity in vitro (28). Interestingly the use of antioxidant (VitE) and antiglutamate therapy (Riluzole and gabapentin) (29) in SOD1 transgenic mice shows that these drugs are effective but at different stages of the disease evolution. In conclusion, a part of the future in ALS therapy could use a combined pharmacological approach associating anti-excitotoxic drugs and antioxidant drugs to try to slow the severe evolution of this devastating disorder.
References
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- Hugon J (1996) ALS therapy : targets for the future. Neurology, 47:S251-254.
- Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature, 362:59-62.
- Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron, 1:621-624.
- Ludolph A, Hugon J, Dwivedi MP, Schaumburg HH, Spencer PS (1987) Studies on the etiology and pathogenesis of motor neuron diseases. Lathyrism: clinical findings in established cases. Brain, 110:149-165.
- Spencer PS, Roy DN, Ludolph A, Hugon J, Dwivedi MP, Schaumburg HH (1986) Lathyrism: evidence for role of the neuroexcitatory aminoacid BOAA. Lancet, 2:1066-1067.
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- Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann. Neurol., 38:73-84.
- Lin CL, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD (1998) Aberrant RNA processing in a neurodegenerative disease : the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron, 20:589-602.
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- Gurney ME, Pu H, Chiu AY, Dal canto MC, Polchow CY, Alexander DD, Caliendo J et al (1994) Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science, 264:1772-1775.
- Bogdanov MB, Ramos LE, Xu Z, Beal MF (1998) Elevated "hydroxyl radical" generation in vivo in an animal model of amyotrophic lateral sclerosis. J. Neurochem., 71:1321-1324.
- Hall ED, Andrus PK, Oostveen JA, Fleck TJ, Gurney ME (1998) Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS. J. Neurosci. Res., 53:66-77.
- Bruijn LI, Houseweart MK, Kato S, Anderson KL, Anderson SD, Ohama E, Reaume AG, Scott RW, Cleveland DW (1998) Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science, 281:1851-1854.
- Beal MF (1998) Mitochondrial dysfunction in neurodegenerative diseases. Biochem. Biophys. Acta, 1366:211-223.
- Hugon J, Hugon F, Esclaire F, Lesort M, Diop AG (1996) The presence of calbindin in rat cortical neurons protects in vitro from oxidative stress. Brain Res., 707:288-292.
- Terro F, Lesort M, Viader F, Ludolph A, Hugon J (1996) Antioxidant drugs block in vitro the CSF neurotoxicity of patients with amyotrophic lateral sclerosis. NeuroReport, 7:1970-1972.
- Lafon-Cazal M, Pietri S, Culcasi M, Bockaert J (1993) NMDA-dependent superoxide production and neurotoxicity. Nature, 364:535-537.
- Volterra A, Trotti D, Tromba C, Floridi S, Racagni G (1994) Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes. J. Neurosci., 14:2924-2932.
- Bowling AC, Schulz JB, Brown RH, Beal MF (1993) Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J. Neurochem., 61:2322-2325.
- Shaw PJ, Ince PG, Falkous G, Mantle D (1995) Oxidative damage to protein in sporadic motor neuron disease spinal cord. Ann. Neurol., 38:691-695.
- Hugon J, Vallat JM, Spencer PS, Leboutet MJ, Barthe D (1989) Kainic acid induces acute and delayed neuronal damages in rat spinal cord. Neurosci. Lett., 104:758-763.
- Liu D, Yang R, Yan X, McAdoo DJ (1994) Hydroxyl radicals generated in vivo kill neurons in the rat spinal cord: electrophysiological, histological, and neurochemical results. J. Neurochem., 62:37-44.
- Carriedo SG, Yin HZ, Weiss JH (1996) Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J. Neurosci., 16:4069-4079.
- Gurney ME, Cutting FB, Zhai P, Doble A, Taylor CP, Andrus PK, Hall ED (1996) Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann. Neurol., 39:147-157.
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