Repurposing antimalarial artesunate for the prophylactic treatment of depression: Evidence from preclinical research

Abstract

Introduction: Several studies have linked inflammation and oxidative stress with the pathogenesis of depression. Artesunate is a commonly used medication to treat malaria and has been shown to produce antioxidant, anti-inflammatory, and immunomodulatory effects. However, its prophylactic effects on depression and depression-related brain pathology are unknown.

Methods: In Experiment 1, using a PC12 cell line, we investigated whether artesunate can prevent hydrogen peroxide (H₂ O₂ )-induced oxidative injury that mimics oxidative stress commonly observed in the depressed brain. Next, using lipopolysaccharide (LPS)-induced mouse model of depression, we investigated whether artesunate can prevent behavioral deficits observed in the open field test, novelty-suppressed feeding test, sucrose preference test, forced swimming test, and tail suspension procedure.

Results: We found that artesunate significantly prevented a H₂ O₂ -induced reduction in PC12 cell activity, suggesting its antioxidant potential. We also found that mice pretreated with artesunate (5, 15 mg/kg) intraperitoneally (i.p.) prior to the LPS (.8 mg/kg, i.p.) treatment showed fewer and less severe depression- and anxiety-like behaviors than the LPS-treated control mice.

Conclusion: Our findings indicate that artesunate produces antioxidant effect, as well as antidepressant and anxiolytic effects. Importantly, our findings first demonstrate that artesunate can prevent LPS-induced depression- and anxiety-like symptoms, strongly suggesting its prophylactic potential in the treatment of depression and, perhaps, other psychiatric disorders associated with inflammation and oxidative stress.

Keywords: artesunate; depression; inflammation; lipopolysaccharide; mouse.

FIGURE 1

Artesunate 0.25–2 μM reversed the decreased cell activity induced by H2O2. (a) Chemical structure of artesunate. (b) Experimental procedure. The PC12 cells were treated with artesunate (0, 0.25, 0.5 1.0, 2.0 μM) and co‐treated with 150 μM H₂O₂ for 24 h. (c) The PC12 cells were treated with artesunate without H₂O₂. (d) The PC12 cells were treated with artesunate and co‐treated with H₂O₂. ***p < .001 as compared to Control group, ^## p < .01 versus H₂O₂ group, n = 5 per group

FIGURE 2

Artesunate exerted antidepressant‐ and anxiolytic‐like effects. (a) Experimental procedure. After 5‐day adaptation period, the mice were injected with vehicle, artesunate 5 mg/kg, 10 mg/kg twice daily for 8 days. From 5th day, behavioral test was conducted. Pretreatment with artesunate had no effect on time spent in the center zone (b) and crossing distance (c) in the OFT, decreased latency time to feeding (d) without affecting the total feeding (e) in the NSF, decreased immobility time (f) without affecting the latency to immobility time (g), and decreased floating time (h) without affecting the latency to floating time (i). *p < .05, **p < .01, ***p < .001 as compared to VEH group. n = 8–11 per group.

FIGURE 3

Artesunate pretreatment significantly blocked LPS‐induced depression‐ and anxiety‐like behaviors. (a) Experimental procedure. After 5‐day adaptation period, mice were injected with artesunate (0, 5, 15 mg/kg) twice daily for 9 days. On day 10, saline or LPS was administered systemically (0 or .8 mg/kg; i.p.). From day 11 to 14, mice were given additional injections of artesunate (0, 5, 15 mg/kg) 30 min prior to each behavioral test. Pretreatment with artesunate had no effect on time spent in the center zone (b) in the OFT. Pretreatment with artesunate significantly blocked the prolonged latency to feeding in the NSF (c), increased immobility time (d) without affecting the latency to immobility time in the TST (e), increased floating time (f) and decreased latency to floating time in the FST (g), decreased source preference (h) and total intake in the SPT (i). *p < .05, **p < .01, **p < .001 as compared to VEH group, ^# p < .05, ^## p < .01, ^### p < .001 as compared to LPS group, n = 8–9 per group.