Up-regulation of adenosine A1 receptor binding in pentylenetetrazol kindling in mice: effects of angiotensin IV

The effects of the hexapeptide angiotensin II (3-8) ANG IV, the selective A1 receptor agonist cyclohexyladenosine (CHA) and the combination of ANG IV + CHA on pentylenetetrazol (PTZ)-generalized seizures; kindling development and maintenance were studied. By using in vitro quantitative receptor autoradiography, the regulation of adenosine A1 receptor density at different time points during the kindling procedure and postkindling period was determined. ANG IV and CHA effectively reduced clonic seizures in PTZ-generalized seizure model, in PTZ-kindled mice as well as during kindling development and a week later by rechallenge with PTZ. Furthermore, coadministration of ANG IV and CHA had a strong anticonvulsant effect, both compounds acting synergistically. A significant increase of adenosine A1 receptor density was detected in somatosensory cortex, hippocampus, amygdala and geniculate nuclei early in the kindling procedure (after the 3rd injection), which persisted at least 1 month after the end of kindling procedure. In addition, a delayed up-regulation of adenosine A1 receptor binding was observed a week after kindling in the mamillary bodies and a month later in the motor cortex. The pretreatment with ANG IV caused a down-regulation of adenosine A1 receptor density to the control level in most time points and brain areas. In conclusion, PTZ kindling-induced increase of adenosine A1 receptor binding at different time points and in specific brain structures might represent an adaptive mechanism for coping with the hyperexcitability typical for this phenomenon. The antiepileptogenic effect of ANG IV could be realized partly through an adenosine-dependent mechanism.