Amyotrophic Lateral Sclerosis

Abstract

This chapter was originally intended to cover both amyotrophic lateral sclerosis (ALS) and multiple sclerosis, but we will concentrate on ALS. There are nonetheless several reports from the literature that ionotropic glutamate receptor antagonists have beneficial effects in animal models of multiple sclerosis (1,7,14,58,71,109) and this could develop into a very promising therapeutic area in the future. The interested reader is referred to the following review (59). However, the evidence for involvement of disturbances in the glutamatergic system in ALS is already convincing and has led to the use of the glutamate release inhibitor riluzole in the treatment of this disease. As such, we felt that a book on the therapeutic potential of ionotropic glutamate receptor antagonists and modulators would be incomplete without a chapter on this disease. RATIONALEALS, commonly called Lou Gehrig's disease, is a devastating neurological disorder characterized by selective upper and lower somatic, but not autonomic, motor neurone degeneration leading to paralysis and eventually death. The diagnosis of ALS requires the presence of both upper and lower motor neurone degeneration and progressive motor dysfunction. ALS occurs in 1 to 2.5 cases per 100,000 population, affects more men than women, and is most commonly diagnosed in middle age. Other functions such as intellectual abilities and sensory perception are preserved. At advanced stages patients become completely disabled, often requiring ventilatory support and feeding by gas-

The amount of neurofilaments aggregated in the cell body is controlled by their increased sensitivity to trypsin-like proteases

“…In Amyotrophic Lateral Sclerosis they precipitate in cell bodies or the proximal part of axons from motor neurons (Hirano, 1991;Corbo and Hays, 1992). They accumulate in Lewy bodies of Parkinson's disease (Hill et al, 1993), in Neurofibrillary Tangles of Alzheimer's disease (Leigh et al, 1989), and following intoxication by aluminium, hexanedione, acrylamide or β,β′-Iminodipropionitrile (IDPN) (Eyer et al, 1989;Leterrier et al, 1992).…”

Cyclin D2 Interacts with cdk‐5 and Modulates Cellular cdk‐5/p35 Activity

“…In addition, tau and NF-H/NF-M side-arms are abnormally phosphorylated on some of these putative cdk-5-targeted residues in certain neurodegenerative diseases. Hyperphosphorylated tau is the major component of paired helical filaments in Alzheimer' s disease (for reviews, see Goedert, 1993;Lee, 1995), and accumulations of neurofilaments containing heavily phosphorylated NF-H/NF-M side-arms as detected by phosphorylation-dependent antibodies are observed in perikarya and proximal axons in motor neurone disease and in Lewy body pathologies (see Hirano, 1991;336 S. GUIDATO ET AL. Pollanen et al, 1993;Trojanowski et al, 1993;Xu et al, 1993).…”

Expression and Activity of Cyclin‐Dependent Kinase 5/p35 in Adult Rat Peripheral Nervous System

“…Because Cdk5 has been shown to phosphorylate some of these in vivo phosphorylation sites of NF (Hellmich et al, 1992;Lew et al, 1992b;Shetty et al, 1993;Sun et al, 1996), it may play important roles in the regulation of cytoskeletal dynamics in neurons under both physiological and pathological conditions. It is known that an altered phosphorylation state of NF is implicated in human neurodegenerative diseases, including Alzheimer disease, Lewy body disease, and motor neuron disease (Hirano, 1991;Trojanowski et al, 1993). Moreover, recent studies using transfection methods and transgenic mice have demonstrated the importance of Cdk5 in neurite outgrowth and neuronal differentiation (Nikolic et al, 1996;Ohshima et al, 1996).…”