TY - JOUR
T1 - Recent advances in the treatment of amyotrophic lateral sclerosis. Emphasis on kynurenine pathway inhibitors
AU - Chen, Yiquan
AU - Meininger, Vincent
AU - Guillemin, Gilles J.
PY - 2009/3
Y1 - 2009/3
N2 - Amyotrophic lateral sclerosis (ALS) is an adult onset, progressive and fatal motor neuron degenerative disease [1]. The aetiology of ALS is currently unknown, though strongly suggested to be multifactorial. Recently, the kynurenine pathway (KP) has emerged as a potential contributing factor [2]. The KP is a major route for the metabolism of tryptophan, generating neuroactive intermediates in the process. These catabolites include the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN) [3] and the neuroprotective NMDA receptor antagonist, kynurenic acid (KYNA) [4,5]. These catabolites appear to play a key role in the communication between the nervous and immune systems, and also in modulating cell proliferation and tissue function [6]. As the cause of ALS is still unknown, there is presently no efficient treatment for it. Currently, Riluzole is the drug of choice but its effect is relatively modest [7]. Targeting the KP, hence, could offer a new therapeutic option to improve ALS treatment [8]. Several drugs that block the KP are already under investigation by our laboratory and others, some of which are in or about to enter clinical trials for other diseases. For example, the KP inhibitors, Teriflunomide (Sanofi-Aventis) and Laquinimod (Teva Neuroscience). Recently, a KP inhibitor has also reached the Japan market as an immu- nomodulative drug [9]: Tranilast/Rizaben® (Angiogen Ltd.) is an anthranilic acid derivative [8]. Finally, the 8-hydroxyquinolinine metal attenuating compounds, Clioquinol and PBT2®, interestingly have close structural similarity with KYNA and QUIN. Such drugs would open a new and important therapeutic door for ALS.
AB - Amyotrophic lateral sclerosis (ALS) is an adult onset, progressive and fatal motor neuron degenerative disease [1]. The aetiology of ALS is currently unknown, though strongly suggested to be multifactorial. Recently, the kynurenine pathway (KP) has emerged as a potential contributing factor [2]. The KP is a major route for the metabolism of tryptophan, generating neuroactive intermediates in the process. These catabolites include the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist, quinolinic acid (QUIN) [3] and the neuroprotective NMDA receptor antagonist, kynurenic acid (KYNA) [4,5]. These catabolites appear to play a key role in the communication between the nervous and immune systems, and also in modulating cell proliferation and tissue function [6]. As the cause of ALS is still unknown, there is presently no efficient treatment for it. Currently, Riluzole is the drug of choice but its effect is relatively modest [7]. Targeting the KP, hence, could offer a new therapeutic option to improve ALS treatment [8]. Several drugs that block the KP are already under investigation by our laboratory and others, some of which are in or about to enter clinical trials for other diseases. For example, the KP inhibitors, Teriflunomide (Sanofi-Aventis) and Laquinimod (Teva Neuroscience). Recently, a KP inhibitor has also reached the Japan market as an immu- nomodulative drug [9]: Tranilast/Rizaben® (Angiogen Ltd.) is an anthranilic acid derivative [8]. Finally, the 8-hydroxyquinolinine metal attenuating compounds, Clioquinol and PBT2®, interestingly have close structural similarity with KYNA and QUIN. Such drugs would open a new and important therapeutic door for ALS.
UR - http://www.scopus.com/inward/record.url?scp=62549117414&partnerID=8YFLogxK
U2 - 10.2174/187152409787601941
DO - 10.2174/187152409787601941
M3 - Review article
C2 - 20021336
AN - SCOPUS:62549117414
SN - 1871-5249
VL - 9
SP - 32
EP - 39
JO - Central Nervous System Agents in Medicinal Chemistry
JF - Central Nervous System Agents in Medicinal Chemistry
IS - 1
ER -