Brain microvascular inflammation induced by Amphetamine involves Angiotensin II AT1 receptors activity

MARCHESE, NATALIA ANDREA; BASMADJIAN, OSVALDO MARTÍN; OCCHIEPPO, VICTORIA BELÉN; BAIARDI, G; BREGONZIO CLAUDIA

PECS

Congreso; FENS REGIONAL MEETING; 2017

Federation of European Neurosciences Societies

Rationale: An increased expression of Angiotensin II AT1 receptors in brain microvessels have been described under certain pathological conditions, such as hypertension. These receptors are the main effector of a locally acting renin-angiotensin system in brain vasculature involved in the regulation of oxidative stress conditions and inflammatory responses. AT1 receptors blockers are known for their safety use in hypertension treatment and for their anti-inflammatory effects by normalization of adhesion molecules, cytokines expression levels and pro-inflammatory transcription factors. On the other hand, the heat shock protein (HSP) family, recognized for its chaperon role over protein folding, display anti-apoptotic effect after noxious stimulus exposure. Particularly, HSP70 is over-expressed after its transcriptional factor activation by increased oxidative stress. Psychostimulants, such as amphetamines (Amph), promote enduring alteration over neural circuits that can be observed long after a challenge administration (drug or stress). Furthermore, their recreational consumption has been associated with brain vascular alterations and inflammatory conditions in cortical brain areas. To this respect we have observed ICAM-1 and AT1 receptors increased expression in medial cerebral artery one week after repeated exposure to Amph. The present work was aimed to identify brain microvascular inflammatory alterations after an Amph sensitization protocol and to elucidate the possible role for AT1 receptors in the onset of these alterations. Methods: male Wistar rats (250-300g) were used. To evaluate the long?term Amph effects over brain vasculature, the animals received a daily Amph (2.5 mg/kg, i.p.) injection for 5 days. To study the participation of AT1 receptors in long?term Amph effects, the AT1 receptor blocker Candesartan (CV 3mg/kg p.o.) was administered for 5 days prior the repeated Amph administration. The inflammatory markers were evaluated after 1 week of withdrawal in basal conditions or evidenced by a challenge exposure (Amph 0.5 mg/kg i.p./ cold exposure 4ºC 4 hs). Brain microvessels were isolated by sucrose gradient and then immunofluorescence was performed against AT1 receptors and HSP70.Results: Amph exposure induced a long lasting increase in AT1 receptors expression at basal conditions. This increase was prevented by previous CV administration. When the animals received a cold exposure challenge elevated levels of AT1 receptors in Amph-treated animals were still evident. Meanwhile, after an Amph challenge, the AT1 receptors expression was exacerbated in all of the experimental groups. Regarding HSP70, there were no differences in its expression at basal conditions. In Amph- treated animals a sensitized HSP70 expression was observed when receiving either an Amph or a cold exposure challenge. Previous AT1 receptors blockade prevented the development of the sensitized response induced by Amph. The present results show that Amph has long-lasting inflammatory effects over brain microvasculature, evidenced as increased AT1 receptors expression and sensitized response of HSP70. The development of Amph-induced microvascular inflammation involved AT1 receptors activation.