Investigation of the relationship between chronic montelukast treatment, asthma and depression-like behavior in mice

Abstract

In 2008, the Food and Drug Administration of the US issued a warning about the neuropsychiatric side effects of montelukast. Previous clinical studies on montelukast have reported conflicting results and, to the best of our knowledge, no experimental studies concerning these side effects had been conducted. In the current study, the effect of montelukast on depression-like behavior in an ovalbumin (OVA)-induced mouse model was investigated. A total of 3 OVA challenges were applied at 2 week intervals for the persistence of asthma. Depression-like behavior was assessed using forced swim tests following each challenge and locomotor activities were evaluated using open field tests. At the end of the current study, plasma montelukast concentrations were measured and the development of asthma and effect of montelukast treatment were histopathologically examined. Inflammation scores that were increased in the OVA mice following all challenges were indicated to be reduced by montelukast treatment. The immobility time of mice increased beginning with the first challenge and this was also reduced by montelukast treatment. Montelukast administration to the control mice did not alter immobility times. Moreover, motor activity of the OVA and montelukast-treated mice were not altered. The results indicated there was no association between chronic montelukast treatment and depression. Furthermore, the chronic administration of montelukast to non-asthmatic mice did not increase immobility. However, depressive behavior increased at all time points in the OVA mice. These results indicated that chronic montelukast treatment is not associated with depression-like behavior and confirmed the association between asthma and depression. Further studies are required to provide an improved understanding of the neuropsychiatric side effects of montelukast.

Keywords: asthma; depression; forced swim test; montelukast; neuropsychiatric side-effects; ovalbumin.

Figure 1

The experimental design for experimental asthma model, montelukast treatments and behavioral and histopathological analysis. OVA, ovalbumin; ML, montelukast; PBS, phosphate buffer saline; FST, forced swim test.

Figure 2

Histopathological images obtained from the lung samples of the (A) OVA and (B) control groups following the first OVA challenge. (C) Total inflammation scores of the lung tissues of the OVA and control groups (n=6/group). (D) Airway resistance was increased in the OVA-treated group compared with control group (after one OVA challenge; n=8/group). (E) The immobility times of the OVA-treated and control mice following the first FST point (n=24/group). (F) Total distance travelled by the mice in the open field test (n=10/group). Data are presented as mean ± standard error of the mean. ^*P<0.05 vs. controls. OVA, ovalbumin; FST, forced swim test.

Figure 3

Histopathological images from the (A) control, (B) OVA and (C) montelukast-treated OVA (20 days of treatment) groups (n=6/group) following the second FST point (40x). (D) Total inflammation scores of the lung tissues of the control, OVA and montelukast-treated OVA groups (n=6/group). Data are presented as mean ± standard error of the mean. ^*P<0.05 vs. controls. OVA, ovalbumin; FST, force swim test.

Figure 4

Immobility times of mice in the control, OVA, montelukast-treated OVA and montelukast-treated controls following the second FST point (n=18/group). Data are presented as mean ± standard error of the mean. ^*P<0.05 vs. controls. ^#P<0.05 vs. the OVA group. OVA, ovalbumin; FST, forced swim test.

Figure 5

Histopathological images from the (A) control, (B) OVA and (C) montelukast-treated OVA groups following the third FST point (n=6/group; magnification, x40). (D) Total inflammation scores of the lung tissues of the control, OVA and montelukast-treated OVA groups (n=6/group). Data are presented as mean ± standard error of the mean. ^*P<0.05 vs. controls. ^#P<0.05 vs. the OVA group. OVA, ovalbumin; FST, forced swim test.

Figure 6

Immobility times of the mice in the control, OVA and montelukast-treated (40 days of treatment) groups (n=12/group). Data are presented as mean ± standard error of the mean. ^*P<0.05 vs. controls. ^#P<0.05 vs. the OVA group. OVA, ovalbumin; FST, forced swim test.