Transgenic rat with overproduction of ubiquitous angiotensin-(1-7) presents neuroprotection in a model of ischemia and reperfusion

• Published in: Brain research bulletin 2023-01, Vol.192, p.184-191
• Main Authors: Kangussu, Lucas Miranda, Almeida-Santos, Ana Flávia, Fernandes, Lorena Figueiredo, Alenina, Natalia, Bader, Michael, Santos, Robson A.S., Massensini, André Ricardo, Campagnole-Santos, Maria José
• Format: Article
• Language: English
• Subjects: Angiotensin-(1-7); Animals; Brain Ischemia - metabolism; Ischemia; Neuroprotection; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Reperfusion Injury - metabolism; Stroke; TG-7371; Transgenic rats
• ISSN: 0361-9230; 1873-2747
• DOI: 10.1016/j.brainresbull.2022.11.017

Recent studies showed that angiotensin-(1-7) has cerebroprotective actions in stroke. In the present study, we aim to test whether tissue overexpression of Angiotensin-(1-7), mainly in the brain provides neuroprotection in a model of ischemia/reperfusion by bilateral common carotid arteries occlusion/reperfusion (BCCAo/R). Evaluation of neurological deficit scores and bilateral asymmetry test (BAT) were performed seven days after transient BCCAo/R in transgenic rats (TG-7371) overexpressing Angiotensin-(1-7) and Sprague-Dawley (SD) rats. To assess blood-brain barrier (BBB) permeability Evans blue dye (EB) was intravenously injected. Cytokine levels were quantified in the whole brain through Elisa assay and oxidative stress was measured 7 days after ischemia. The expression of AT1 and Mas receptors and inducible nitric oxide synthase (iNOS) was evaluated by RT-PCR. Neurological deficits were observed in both SD-BCCAo/R and TG-BCCAo/R, contrasting to sham-operated groups. However, TG-BCCAo/R showed a significant lower neurological score and latency in BAT when compared with SD-BCCAo/R. BBB integrity in TG-BCCAo/R was improved, since these animals showed lower extravasation of EB than SD-BCCAo/R. Interestingly, TG-BCCAo/R presented lower levels of pro-inflammatory cytokines when compared to SD-BCCAo/R. Levels of IL-10 were higher in SD-BCCAo/R than in SD control and even higher in TG-BCCAo/R. TG-BCCAo/R animals presented decreased levels of TBARS and increase in SOD activity and GSH levels when compared to SD sham rats. RT-PCR results showed higher levels of AT1 receptor and iNOS in SD-BCCAo/R compared to TG-BCCAo/R, but no difference was observed for Mas receptor. The present study shows that lifetime increase in cerebral expression of an Ang-(1-7)-producing fusion protein induces neuroprotection in experimental global cerebral ischemia and reperfusion, reassuring that, pharmacological strategies leading to increase in Ang-(1-7) can be an additional tool for stroke therapy. •Higher levels of Ang-(1-7) causes neuroprotection in rats submitted to BCCAo/R.•TG-7371 showed improved behavior on neurological tests after BCCAo/R.•TG-7371 ameliorated inflammation and oxidative stress in brain after BCCAo/R.•TG-7371 presented decreased AT1 receptor and iNOS expression in brain after BCCAo.