The National Science Foundation's (NSF) Tokyo Office periodically receives and disseminates reports on research developments in Japan that are related to the Foundation's mission. NSF-sponsored researchers currently working in Japan prepare many of these reports. These reports present information for use by NSF program managers and policy makers; they are not statements of NSF policy. .
Mr. Raymond D. Price, a Ph.D. candidate in the Department of Pharmacology, Vanderbilt University, Nashville, TN, prepared the following report. Mr. Price was a participant in the 1999 Summer Institute, sponsored by NSF/NIH/USDA in the U.S. and the Science and Technology Agency and the Japan Science and Technology Corporation in Japan. Dr. Kazuo Tsukidate, DSD Research Laboratories of the Eisai Tsukuba Laboratories, hosted Mr. Price. Mr. Price can be reached via email at: Ray.Price@mcmail.vanderbilt.edu
Multiple sclerosis (MS) is a common neurodegenerative disease of the central nervous system (CNS). Little is known about the factors which contribute to its variable course and the cause of the disease remains uncertain. Lesions in MS are primarily inflammatory reactions against oligodendrocytes, the cells that provide axon sheathing. Treatment options for this disease are limited. For decades, brief courses of corticosteroids have been used to speed recovery from a relapse. Currently, there is evidence that administration of b-interferons may delay progression of clinical worsening. However, these current therapies are immunomodulatory, require subcutaneous or intramuscular injection, and can have side effects. Thus, new therapies and treatment options are needed.
Excitatory amino acids have been implicated in the pathogenesis of a number of neurodegenerative diseases, particularly as an excitotoxin causing neuronal degeneration following ischemia and CNS trauma. While the link between glutamate-mediated cell death and demyelinating disorders is less clear, recent data suggest that in situ activation of AMPA receptors may account for the oligodendrocyte disruption and/or death seen in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In addition, work with the selective AMPA/kainate receptor antagonists NBQX and MPQX in EAE suggests these compounds could have novel therapeutic benefit for the treatment of MS. In addition, these compounds are orally active, non-immunomodulatory, and can directly protect oligodendrocytes, the cells which are the primary target of immune activity in MS.
Objectives
ASAP 187, an AMPA/kainate antagonist, showed high potency and selectivity in in vitro studies. The objective of this study was to determine the maximum tolerated dose (MTD) for further longer-term studies and to characterize any toxic potential.
Study Design
ASAP 187 and vehicle (distilled water) was administered orally once per day to 8-week-old IGS rats (3 male, 3 female rats/group) at doses of 30, 100, and 300 mg/kg for four days. All surviving rats were sacrificed on Day 5.
Measurements
Clinical signs, body weight and food consumption were recorded from Day 1 to Day 5.Hematology and clinical chemistry were recorded on Day 5. Postmortem measurements included macroscopic investigation, histopathology, and determination of organ weights.
Results
Administration of ASAP187 was well tolerated with no toxicity observed at 30mg/kg. Immediately after administration, animals in the intermediate (100 mg/kg) and high dose (300 mg/kg) groups showed abnormal gait and prone or lateral position. One animal in the high dose group died after the initial administration. Clinical signs diminished in severity with subsequent administrations, such that there were almost no clinical signs observed on Day 4 of administration. Stomach ulcer/erosion and adhesion to peritoneal organs was observed in one male rat in the high dose group. The same animal also showed decreased body weight and food consumption. One female rat in the high dose group showed stomach ulcer/erosion. Neutrophil counts were elevated in one male and one female rat in the high dose groups. Liver weight increased in the female high dose group. There was no abnormal histopathology except for observations of stomach ulcers.
Conclusions
The No-Adverse-Effect-Level (NOEL) for ASAP187 is 30 mg/kg. The MTD for future long-term toxicity and functional studies should be 100 mg/kg.