G. Ceresoli et al., METABOLISM OF [5-H-3]KYNURENINE IN THE DEVELOPING RAT-BRAIN IN-VIVO -EFFECT OF INTRASTRIATAL IBOTENATE INJECTIONS, Developmental brain research, 100(1), 1997, pp. 73-81
Two metabolites of the kynurenine pathway of tryptophan degradation, t
he neurotoxin quinolinic acid (QUIN) and the neuroprotectant kynurenic
acid (KYNA), may play a role in the initiation or propagation of brai
n diseases. In order to study their disposition during the acute and c
hronic stages of neurodegeneration, effects of an excitotoxic insult o
n the de novo synthesis of several kynurenine pathway metabolites were
examined in vivo. Neuronal injury and lesions were produced in 7-day
(PND 7), 14-day (PND 14) and young adult rats by an intrastriatal inje
ction of the excitotoxin ibotenic acid. At 2 h, 2, 7 and 28 days later
, the formation of tritiated KYNA, 3-hydroxykynurenine (3HK), xanthure
nic acid and QUIN was assessed after an acute intrastriatal injection
of their common bioprecursor, [5-H-3]kynurenine. In all three age grou
ps, the acute insult resulted in a shift towards enhanced KYNA formati
on, as indicated by 2-4 fold decreases in the 3HK/KYNA and QUIN/KYNA r
atios in ibotenate-treated striata. At later post-lesion intervals, ag
e-specific several-fold changes were observed in the flux through both
the KYNA and QUIN branches of the kynurenine pathway. With aging, kyn
urenine conversion to QUIN and especially to 3HK, became increasingly
more prominent, though KYNA synthesis was substantially activated as w
ell. The acute toxin-induced changes in kynurenine metabolism, the pro
pensity of the lesioned immature striatum to increase KYNA production
preferentially, and the pronounced lesion-induced long-term increases
in cerebral KYNA, 3HK and QUIN formation may participate in the modula
tion of NMDA receptor function following injury. In particular, change
s in the production of these kynurenine pathway metabolites may play a
role in mechanisms involved in endogenous neuroprotection, delayed ne
urodegeneration and regenerative processes.