Διερεύνηση της επίδρασης των αντιφλεγμονωδών φαρμάκων στο κεντρικό νευρικό σύστημα επιμυών - αναστολείς της κυκλοξυγενάσης-2 (Doctoral thesis)
In the present study the effects of cyclooxygenase-2 (COX-2) inhibitors on the rat Central Nervous System were examined. The aim of the study was to investigate further possible effects of etoricoxib a selective COX-2 inhibitor on behavioral and neurochemical functions and if the action of etoricoxib can be altered by the administration of serotonin’s agonists and antagonist. Another goal of this particular study was to investigate a possible effect of etoricoxib on behavioral and neurochemical functionss after inuced inflammation. For this reason, a number of experiments were held in which three-month years-old male Wistar rats were used. All substances and drugs were intraperitoneal injected to experinmental subjects. The spontaneous behavior was recorded with an automated open-field behavioral recorder system (Open-Field test) in which horizontal and vertical mobility is monitored. For the determination of neurotransmitters a High-Pressure Liquid Chromatogrphy (HPLC) was used. Moreover, at the experimental protocol of lipopolysacharide (LPS) administration, the body temperature was recorded and the levels of interleukin-6 (IL-6) in blood were determined in rats.. The results showed that etoricoxib one hour after its administration reduced rat mobility and dopaminergic function while increased noradrenaline (NA) levels and serotonergic function in specific rat brain regions. However, after the completion of three hours from its administration, most of the effects of etoricoxib were suppressed. The effect of etoricoxib on mobile activity and neurochemical transmission was investigated further using serotonin (5-HT) agonists and antagonists. Even though, 5-HT1A agonist did not influence etoricoxib action on rat mobile activity, nevertheless, completely abolished the action of etoricoxib on dopaminergic and serotonergic function as well as on the NA levels in the rat brain regions included in the study. On the other hand, 5-HT1A antagonist abolished the action of etoricoxib only on the vertical mobile activity while abolished the action of etoricoxib on NA levels and on serotonergic function in specific rat brain regions. With regard to 5-HT2A receptos it appears that 5-HT2A agonist abolished the effects of etoricoxib on rat mobility and on dopaminergic function at the prefrontal cortex as well as on the serotonergic function in all rat brain regions being studied. On the contrary, the 5-HT2A antagonist had no effect on etoricoxib-induced changes on rat mobility while inhibited partially the etoricoxib action on neurochemical changes after etoricoxib administration. LPS administration induced a decrease on mobile activity in rats but it was partially reversed by etoricoxib. Moreover, LPS caused neurochemical changes showing tissue differentiation. It is noteworthy that neurochemical effects of LPS were reversed by the selective COX-2 inhibitor, etoricoxib. Finally, the adminisration of LPS induced inflamation which was obvious by the elevated body temperature and IL-6 levels in the blood. The effect of inflammation on body temperature was reversed by the selective COX-2 inhibitor but not that of IL-6. In conclusion, the selective COX-2 inhibitor, etoricoxib induced changes on behavioral factors as well as on neurochemical functions focused on the serotonergic transmission. Further investigation of the mechanism that relies on this action of etoricoxib showed implication of 5-HT1A and 5-HT2A receptors with an important role of 5-HT2A. Finally, etoricoxib can reverse the LPS-induced changes on dopaminergic and serotonergic fuction as well as the reduced mobility and increased body temperature except from elevated production of IL-6. The involvement of 5-HT2A receptors in inflammation and in the effects of etoricoxib’s action, revealed a crucial interaction between prostaglandins and serotonin, supporting a subsequent action on these receptors and the opposite, that needs to be examined further.
|Institution and School/Department of submitter:||Πανεπιστήμιο Ιωαννίνων Σχολή Ιατρικής. Τμήμα Ιατρικής Τομέας Λειτουργικός - Κλινικοεργαστηριακός Εργαστήριο Φαρμακολογίας|
|Subject classification:||Νευρικό σύστημα|
|Keywords:||Κυκλοξυγενάση - 2,Αντιφλεγμονώδη φάρμακα,Κεντρικό νευρικό σύστημα|
|Appears in Collections:||Διδακτορικές Διατριβές|
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