The Effect of Systemic Nitroglycerin Administration on the Kynurenine Pathway in the Rat

Abstract

The primary headache disorders include migraine, which is one of the most frequent neurological disorders, which influences more than 14% of the whole population. Despite the research efforts, its exact pathomechanism is not fully revealed, but evidence points to the role of glutamate and its receptors. Kynurenic acid is an endogenous glutamate receptor antagonist produced by the kynurenine pathway (KP). Tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) convert l-tryptophan to N-formyl-l-kynurenine, to be further transformed to l-kynurenine. Kynurenine aminotransferase-II (KAT-II), l-kynurenine hydrolase (KYNU), and l-kynurenine 3-monooxygenase (KMO) are key enzymes in the later steps of the KP. Nitroglycerin (NTG) administration serves as both human and animal model of migraine, causing the activation and sensitization in the trigeminal system. A previous study demonstrated a reduction of KAT-II expression following NTG administration in animals. The goal of current tests was to identify the potential modulatory effect of NTG on other metabolizing enzymes of the KP in the caudal trigeminal nucleus (TNC) of rats. Four hours following the intraperitoneal injection of NTG (10 mg/kg), the rats were perfused transcardially and the TNC was extracted for Western blotting. Western blot studies revealed that the expression of TDO2, IDO1, KYNU, and KMO decreased in the TNC. The results demonstrated that NTG is able to downregulate the KP, with a potential influence on the glutamatergic system as well, contributing to the development of trigeminal activation and sensitization in animals.

Glutamate and Its Receptors as Therapeutic Targets for Migraine

“…It has been hypothesized that kynurenines could play a role in migraine by modulating glutamatergic activity [17]. In animal models of migraine, nitroglycerine downregulates the kynurenine pathway [18] while kynurenines have been shown to reduce nitroglycerinevoked hyperalgesia [19] and cortical spreading depression [20]. Altered levels of kynurenines have been reported in chronic migraine patients [21].…”

Interactions between the Kynurenine and the Endocannabinoid System with Special Emphasis on Migraine

“…In this model, NTG was able to decrease the expression of kynurenine aminotransferase II (KATII) [ 45 ], which is the key enzyme of KYNA production. In a recent study, it was also shown that NTG altered the expression of other enzymes of the KP, namely TDO, IDO, KYNU and KMO, suggesting that NTG/NO has an influence on the KP [ 46 ].…”

Kynurenine‐3‐monooxygenase: A new direction for the treatment in different diseases

“…Moreover, Rojewska, Ciapala, Piotrowska, Makuch, and Mika () found that IDO2 and KMO may be the new treating targets for neuropathic pain. Nagy‐Grocz et al () also found that the mechanism of nitroglycerin on treating primary headache may be related to KP regulated by KMO. NMDAR is an important intermediate substrate for KMO treatment of ischemic stroke, and the upstream product IDO of KMO is also a problem worthy of study.…”