Kynurenine in combination with probenecid mitigates the stimulation-induced increase of c-fos immunoreactivity of the rat caudal trigeminal nucleus in an experimental migraine model

Abstract

Nitroglycerin, often used as a migraine model, results in increased number of c-fos immunoreactive secondary sensory neurons in the caudal trigeminal nucleus. Since synapses between first- and second-order trigeminal neurons are mediated by excitatory amino acids, NMDA receptors are presumably inhibited by kynurenic acid, the only known endogeneous NMDA receptor antagonist. Although kynurenic acid does not cross the BBB, its precursor, kynurenine, if combined with probenecid, crosses it readily. Systemic kynurenine + probenecid treatment significantly diminishes nitroglycerin-induced increase of c-fos immunoreactivity in the brainstem.

Tryptophan Catabolites and Migraine

“…The same combination was applied in the nitroglycerine induced model (NTG model), where it was also able to decrease the activation of the trigeminal system [137]. These results suggest that elevated KYNA levels may be protective against trigeminal hyperactivity.…”

Migraine, Neurogenic Inflammation, Drug Development - Pharmacochemical Aspects

“…A possible site of action of KYNA might be the TG [134,136]. In the TNC, KYNA was not able to attenuate nitroglycerininduced activation [137], as KYNA can poorly penetrate the BBB. In turn, L-kynurenine (L-Kyn) combined with probenecid were able to mitigate the activation of second-order neurons in the TNC both in the model of electrical stimulation of the TG [137], and in the nitroglycerin model [138].…”

“…In the TNC, KYNA was not able to attenuate nitroglycerininduced activation [137], as KYNA can poorly penetrate the BBB. In turn, L-kynurenine (L-Kyn) combined with probenecid were able to mitigate the activation of second-order neurons in the TNC both in the model of electrical stimulation of the TG [137], and in the nitroglycerin model [138]. In order to facilitate BBB penetration, novel KYNA-derivates are being synthesized by our research group (Fig.…”

Testing of neuroprotective compounds in a transgenic mouse model of Huntington's disease

“…The lack of significant effects on survival in the case of L-KYN could be due to several reasons. Although L-KYN has been found to be protective alone in brain ischaemia models or in combination therapy with probenecid in a migraine (Knyihar-Csillik et al, 2007) or ischaemia model (Robotka et al, 2008), these beneficial effects were seen after an acute event with sudden onset. The transformation of L-KYN in these acute conditions is probably mediated mainly towards KYNA production.…”