br Materials and methods br

Materials and methods
Results
Discussion Our results revealed that LPS injection in rats impaired fear memory in the PA task. This results are in agreement with the most of previous studies reported that following acute [23,24,39,[45], [46], [47]] or chronic systemic Tanshinone IIA---sulfonic sodium [30] fear learning and memory were disrupted. A large body of evidence indicates that the basolateral amygdala and hippocampus are necessarily involved in the learning and storage of fear memory in the inhibitory avoidance [48,49]. It has been reported that the intra-amygdala injection of TNF-α impairs auditory-cued fear memory [50]. Interestingly, pretreatment with losartan effectively attenuated the negative effects of inflammation on the retrieval of passive avoidance behavior. There is no specific study to investigate the effect of ARBs on the LPS induced passive avoidance behavior disruption, however, our finding is in agreement with previous studies which indicated that AT1R blocked by telmisartan increased avoidance latency in stressed rats [51]. Also, it has been reported that captopril an ACE inhibitor prevented from the adverse effects of inflammation on passive avoidance behavior [23]. To evaluate motivational behavior we used SPT and FST and the findings showed that LPS injection induced anhedonia in the SPT and increased immobility time in the FST. Our results are in line with previous studies that reported anhedonia induced by LPS administration is long lasting effect which is can persist long even after resolving the inflammation [27,38,52,53]. Interestingly, pretreatment with losartan, improved sucrose preference in the LPS-injected animals. In contrary, it has been reported that while treatment with losartan tended to increase the preference to sweet solution in the control rats, it was unable to prevent anhedonia in the status epilepticus rats [54]. Moreover, it has been reported that both single LPS injection [52,55] and chronic LPS injection [56] induced depressive-like behavior by increasing immobility time in FST. There are extensive evidence supporting the role of inflammation in depression including experimental and preclinical data. For instance, it has been reported that expression of pro-inflammatory cytokines, chemokines and soluble adhesion molecules are increased in peripheral blood and cerebrospinal fluid of patients with major depressive disorder [57]. Pretreatment with losartan decreased depressive-like behavior in the LPS treated rats in the present study. It has been reported that losartan decreased depressive-like behavior tested in FST in stressed mice [58]. In contrast to these findings, it has been reported that losartan is unable to reduced depressive-like behavior in the status epilepticus rats [54]. Pretreatment with losartan reversed the deleterious effect of LPS injection in the weight gain which this effect can also reflect a successful anti-inflammatory action of losartan. Our results are in line with previous studies showing that ARBs prevented from deleterious effects of inflammation in the weight gain [17]. On the other hand, it has been reported that ARBs can also reduce weight gain but this required high doses of ARBs [59] and it seems that ARBs in low dose don't have any negative effects on weight gain. The biochemical data of the present study revealed that LPS injection increased IL-6 and oxidative stress markers in the cortex and hippocampus. Our results are in line with previous studies indicating that systemic LPS injection increased pro-inflammatory cytokines levels in the brain in either acute [8,17,27,53,60,61] or chronic inflammation [56,62]. Moreover, our results corroborate previous studies which reported that blocking of AT1R prevented from neuroinflammation by inhibiting microglial activation [18,20,63], cytokine production [18] and oxidative stress [64,65]. Histochemical analyses of microglial activation such as ionized calcium-binding adaptor protein-1 (iba1) and iNOS activity (M1 phenotype marker) and Arg-1 and chitinase (M2 phenotype marker) will be useful to better understanding of anti-inflammatory mechanism of losartan. However, different mechanisms have been purposed for anti-inflammatory effects of AT1R blocking which is discussed at the following.