Method for interviewing neuronal death using sulfasalazine

Details Method for interviewing neuronal death using sulfasalazine Method for interviewing neuronal death using sulfasalazine

2000-04-21

2003-02-18

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06521640

ABSTRACT:

FIELD OF THE INVENTION
The present invention is related to a new use of sulfasalazine, and in particular, is related to a method for preventing neuronal death in brain diseases by administering sulfasalazine.
BACKGROUND OF THE INVENTION
<Excitotoxicity and Brain Diseases>
Excess activation of ionotropic glutamate receptors sensitive to N-methyl-D-asparte (NMDA receptors) produces neuronal death and has been known to mediate various neurological diseases [Choi, Neuron 1:623-634 (1988)]. Glutamate, an excitatory neurotransmitter, is massively accumulated in brain subjected to hypoxic-ischemic injuries, which activates ionotropic glutamate receptors permeable to Ca
2−
and Na
+
and then causes neuronal death [Choi and Rothman.
Annu Rev Neurosci
13:171-182 (1990)]. Antogonists of NMDA receptors remarkably attenuate brain injury following hypoclycemia, hypoxia, or hypoxic-ischemia [Simon, Swan, Griffiths, and Meldrum.
Science
226:850-852 (1984); Park, Nehls, Graham, Teasdale, and McCulloch,
Ann Neurol
24:543-551 (1988); Wieloch,
Science
230:681-683 (1985); Kass, Chambers, and Cottrell,
Exp. Neurol
, 103:116-122 (1989); Weiss, Goldberg, and Choi,
Brain Res.
380:186-190 (1986)]. Thus, NMDA receptor antagonists possess therapeutic potentials to protect brain against hypoglycemia, hypoxia, and hypoxic-schemic injuries.
Excitotxicity appears to contribute to neuronal degeneration following traumatic brain injury (TBI). Levels of quinolinic acid, an endogenouis agonist of NMDA receptors, are increased 5- to 50-fold in human patients with TBI [E. H. Sinz, P. M. Kochanek, M. P. Heyes, S. R. Wisniewski, M. J. Bell, R. S. Clark, S. T. DeKosky, A. R. Blight, and D. W. Marion]. Quinolinic acid is increased in the cerebrospinal fluid and associated with mortality after TBI in humans [
J. Cereb. Blood Flow Metub
. 18:610-615, (1998)]. In animal models of brain trauma, levels of glutamate and aspartate were markedly increased. Faden, Demediuk, Panter, and Vink [
Science
244:798-800 (1989)]. Glutamate release was also observed in rat spinal cord following impact trauma [Demediuk, Daly, and Faden. J Neurochem J.
Neurochem
. 52:1529-1536 (1989)]. NMDA receptor antagonists attenuate neuronal death following traumatic brain or spinal cord injuries [Faden, Lemke, Simon, and Noble.
J. Neurotrauma
. 5:33-45(1988); Okiyama, Smith, White, Richter, and McIntosh.
J. Neurotrauma
. 14:211-222 (1997)].
Glutamate plays a central role in the induction and the propagation of seizures. Dingledine, McBain and McNamara [
Trends. Pharamacol. Sci
. 11:334-338 (1990); Holmes.
Cleve. Clin. J. Med
. 62:240-247(1995)]. NMDA receptor antagonists were shown to act as anticonvulsants and antiepileptogenic drugs in various models of epilepsy [Anderson, Swartzwelder, and Wilson,
J. Neurophysiol
. 57:1-21 (1987); Wong, Coulter, Choi, and Prince.
Neurosci. Lett
. 85:261-266 (1988); McNamara, Russel, Rigsbee, and Bonhaus,
Neuropharmacology
27:563-568 (1988)].
Amyotrophic lateral sclerosis (ALS) is accompanied by degeneration of both upper and lower motor neurons and marked neurogenic atrophy, weakness, and fasciculation. While the pathogenesis of ALS remains to be resolved, excitotoxicity has been expected to participate in the process of ALS. In particular, ALS patients show increased levels of extracellular glutamate and defects in glutamate transport. Administration of excitotoxins mimicked pathological changes in the spinal cord of ALS patients [Rothstein.
Clin. Neurosci
. 3:348-359 (1995); [konomidou, Qin, Labruyere, and Olney
J. Neuropahol. Exp. Neurol
. 55:211-224 (1996)].
Antagonizing NMDA receptors appears to be applied to treat Parkinson's disease (PD). Several antagonists of NMDA receptors protect dopaminergie neurons from the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [Lange, Losehmann, Sofie, Burg, Horowski, Kalveram, Wachel, and Riederer,
Naunym Schmiedebergs Arch. Pharmacol
. 348:586-592 (1993); Brouillet and Beal.
Neuroreport
. 4:387-390 (1993)]. NMDA receptor antagonists also ameliorate levodopa-induced dyskinesia and thus can improve the therapeutic effects of levodopa [Papa and Chase.
Ann. Neurol
. 39:574-578 (1996) Marin, Papa, Engber, Bonastre, Tolosa, and Chase.
Brain Res
. 736:202-205 (1996)]. Two NMDA receptor antagonists, memantine and dextromethophan, have been proved beneficial in treating PD patients [Verhagen, Del Dotto, Natte, vand den Munekhof, and Chase,
Neurology
51:203-206 (1998); Merello Nouzeilles, Cammarota, and Leiguarda,
Clin. Neuropharmacol
. 22:273-276 (1999)].
Huntington's disease (HD) is a progressive neurodegenerative disease predominantly affecting small- and medium-sized interneurons but sparing NADPH-diaphorase neurons containing somatostatin and neuropeptide in the striata. These pathological features of HD are observed in the striatal tissues following the intrastriatal injections of quinolinic acid or cultured striatal neurons exposed to NMDA, raising the possibility that NMDA receptor-mediated neurotoxicity contributes to selective neuronal death in HD [Koh, Peters, and Choi,
Science
234:73-76 (1986)]. Beal, Kowall, Ellison, Mazurek, Swartz, and Martin,
Nature
321:168-171 (1986); Beal, Ferrante, Swartz, and Kowall,
J. Neurosci
. 11:1649-1659 (1991)].
<Free Radicals and Brain Diseases>
Free radicals are produced in degenerating brain areas following hypoxic-ischemia or traumatic brain and spinal cord injuries [Hall and Braughler,
Free Rudic. Biol. Med
. 6:303-313 (1989); Anderson and Hall,
Ann. Emerg. Med
. 22:987-992 (1993); Siesjo and Siesjo,
Eru. J. Anaesthesiol
. 13:247-268(1996); Love,
Brain Pathol
9:119-131 (1999)]. Antioxidants or maneuvers scavenging free radicals attenuate brain damages by hypoxic-ischemia or traumatic injuries [Faden,
Pharmacol. Toxicol
. 78:12-17 (1996); Zeidman, Ling, Ducker, and Ellenbogen,
J. Spinal. Disord
. 9:367-380 (1996); Chan,
Stroke
27:1124-1129 (1996); Hall,
Neurosurg. Clin, N. Am
. 8:195-206 (1997)]. Extensive evidence supports that free radials can be produced in brain areas undergoing degeneration in neurodegenerative diseases possibly due to point mutations in Cu/Zn superoxide dismutase in ALS, decreased glutathione level and increased iron level in PD, accumulation of iron in AD, or mitochondrial dysfunction in HD [Rosen, Siddique, Patterson, Figlewicz, Sapp, Hentati, Donaldson, Goto, O'Regan, and Deng,
Nature
362:59-62 (1993); Jenner and Olanow,
Neurology
47:S161-S170 (1996); Smith, Harris, Sayre, and Perry,
Proc. Natl. Acad. Sci. U.S.A
. 94:9866-9868 (1997); Browne, Ferrante, and Beal,
Brain Pathol
. 9:147-163 (1999)]. Accordingly, antioxidants have been neuroprotective against such neurodegenerative diseases. Jenner,
Pathol. Biol. (Paris.)
44:57-64 (1996); Beal,
Ann. Neurol
. 38:357-366 (1995); Prasad, Cole, and Kumar,
J. Am. Cott. Nutr
. 18:413-423 (1999); Eisen and Weber,
Drugs Aging
14:173-196 (1999); Grundman,
Am. J. Clin. Nutr
. 71:630S-636S (2000)].
<Zine and Brain Diseases>
Zn
2+
mediates neurodegenerative process observed in seizure, ischemia, trauma, and Alzheimers diseases (AD). The central administration of kainate, a seizure-inducing excitotoxin, causes the translocation of Zn
2+
into postsynaptic degenerating neurons in several forebrain areas [Frederickson, Hernandez, and McGinty.
Brain Res
. 480:317-321 (1989)]. Blockade of Zn
2+
translocation with Ca-EDTA attenuates neuronal loss following a transient forebrain ischemia or traumatic brain injury [Koh, Suh, Gwag, He, Hsu, and Choi,
Science
272: 1013-1016 (1996); Suh, Chen, Motamedi, Bell, Listiak, Pons, Danscher, and Frederickson,
Brain Res
. 852:268-273 (2000)]. Zn
2−
is observed in the extracellular plaque and degenerating neurons in AD, which likely contributes to neuronal degeneration in AD [Bush, Pett

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