Licofelone Attenuates LPS-induced Depressive-like Behavior in Mice: A Possible Role for Nitric Oxide

Abstract

-PURPOSE: Licofelone, a dual cyclooxygenase/5-lipoxygenase inhibitor, possesses antioxidant, antiapoptotic, neuroprotective, and anti-inflammatory properties. The aim of the present study was to investigate the effect of licofelone on lipopolysaccharide (LPS)-induced depression in a mouse model and also a possible role for NO. METHODS: To elucidate role of NO on this effect of licofelone (5 and 20 mg/kg, i.p.), L-NAME, a nonspecific NO synthase (NOS) inhibitor; aminoguanidine (AG), a specific inducible NOS (iNOS) inhibitor; 7-nitroindazole (7-NI) a preferential neuronal NOS inhibitor (nNOS) and; L-arginine (L-Arg), as a NO donor, were used. The animal's behaviors were evaluated employing forced swimming test (FST), tail suspension test (TST) and open field test (OFT). RESULTS: LPS (0.83 mg/kg, i.p.) induced depressive-like behavior increasing immobility time in FST and TST. Conversely, licofelone (20 mg/kg i.p.) reversed the depressive effect of LPS and lowered the immobility time in FST and TST. On the other hand, pretreatment with L-Arg also reversed the antidepressant-like effect of licofelone (20 mg/kg) in FST and TST. On the other hand, L-NAME (10 and 30 mg/kg), AG (50 and 100 mg/kg) and 7-NI (60 mg/kg) could potentiate licofelone (5 mg/kg) and lowered the immobility duration. CONCLUSIONS: NO down-regulation possibly through iNOS and nNOS inhibition may involve in the antidepressant property of licofelone.

Rosiglitazone attenuates lipopolysaccharide-induced depressive-like behavior and cognitive deficits in mice

“…In preclinical studies, the cytokine inducer LPS has been demonstrated to promote behavioral alterations in mice, some of which, resemble depressive symptoms in humans [33]. Using two validated depression tests in rodents, the FST and the TST, we observed that LPS administration increased immobility time indicating an increase in depressive-like behavior, which is in agreement with previous studies [34,35]. Apart from the classical depressive symptoms, evidence indicates that depressed patients also display cognitive impairment [36].…”

Inflammation‐driven brain and gut barrier dysfunction in stress and mood disorders

“…LPS treatment causes expression of certain depression‐like symptoms in rodents (Yirmiya, 1996) and is clinically relevant to human depression (Alvarez‐Mon et al., 2019). Administration of LPS is frequently used to study neuroinflammation‐associated diseases in mice (Zhao et al., 2019); ergo this model enables a focus on the inflammatory‐related pathways in depression (Dantzer et al., 2008; Mousavi et al., 2019; Remus & Dantzer, 2016; Walker et al., 2019). Systemic LPS can trigger a pro‐inflammatory response and microbicidal responses through engagement of pattern recognition receptors such as Toll‐like receptors on immune cells (Amarante‐Mendes et al., 2018).…”

Involvement of N-Methyl-D-Aspartate Receptors in the Anticonvulsive Effects of Licofelone on Pentylenetetrazole-Induced Clonic Seizure in Mice

“…15 Furthermore, licofelone has been shown to exert antidepressant-like effects probably through its anti-inflammatory property. 16 In line with this, other COX inhibitors, either selective (nimesulide, rofecoxib and celecoxib) or non-selective (aspirin, naproxen), have been examined in animal seizure models, suggesting an elevation in the seizure threshold. 45 In the present study, the effects of acute administration of five different doses of licofelone (1, 3, 5, 10, and 20 mg/kg, i.p.)…”

“…15 Furthermore, licofelone can exert antidepressant-like ef-fects probably due to its anti-inflammatory properties. 16 Collectively, these studies point toward an instrumental therapeutic role of dual COX/5-LOX inhibitors in CNS disorders in which oxidative stress plays a key role. Consistent with this notion, the protective effect of licofelone in epileptic disorders has been investigated in recent years.…”