Role of spin trapping and P2Y receptor antagonism in the neuroprotective effects of 2,2'-pyridylisatogen tosylate and related compounds.
2,2'-Pyridylisatogen tosylate (PIT) is both an allosteric modulator of P2Y receptors, and an immine oxide, acting as a spin trap for free radicals. PIT (10 mg kg(-1), i.p.) was found to be a powerful neuroprotective agent in protecting against the lesions induced by 15 micro g S-bromo-willardiine injected into the cortex or white matter of 5-day-old mice pups. As the multiple effects of PIT may induce both beneficial and deleterious effects, a reanalysis of the structure-activity relationship was undertaken. PIT (50 micro M) and 2,3'-pyridylisatogen were potent antagonists of responses to ATP in the taenia preparation of the guinea-pig caecum, but 2,3'-nitrophenylisatogen was not. The reactive immine oxide group could be substituted by a keto moiety (N-(2'-pyridyl)phthalide) while maintaining antagonism of responses to ATP, equivalent to PIT. Thus, antagonism of P2Y receptors was not restricted to the isatogen nucleus. Other spin traps did not antagonise P2Y receptors, although dimethyl-pyrroline-N-oxide (DMPO) increased the sensitivity of responses to ATP. Both N-(2'-pyridyl)phthalide and 2,3'-nitrophenylisatogen was less neuroprotective than PIT (10 mg kg(-1), i.p.) in protecting against the S-bromo-willardiine-induced lesions in mice, implying that both antagonism of P2Y receptors and the immine oxide moiety may be important for the neuroprotective effects of PIT. However, the usefulness of the neuroprotection was limited because, in motoneurones obtained from rat embryos, PIT (10-100 micro M) exacerbated cell death.
Menton
Kevin
K
Institute of Pharmacy, Chemistry and Biomedical Sciences, School of Sciences, University of Sunderland, Sunderland, SR1 3SD, UK.
Spedding
Michael
M
Gressens
Pierre
P
Villa
Pascal
P
Williamson
Toni
T
Markham
Anthony
A
D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D007510:Isatin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D019097:Spin Trapping; D013329:Structure-Activity Relationship
D018696:Neuroprotective Agents; D058919:Purinergic P2 Receptor Antagonists; C009128:2,2'-pyridylisatogen tosylate; D007510:Isatin