Safety assessment of doxycycline after an oral long-term administration in rats

Doxycycline has been widely studied for off-label use as neuroprotective and is capable to reduce oxidative stress in several neurodegenerative diseases. However, it is necessary to assess the safety of long-term exposure to doxycycline once neurodegenerative diseases generally require chronic treatments. Thus, we evaluated the safety of doxycycline in chronic use through hematological, biochemical, redox, and histological analysis. Male Wistar rats were divided into two groups: control (saline 0.9%) and experimental (10 mg/kg doxycycline/day), for 93 days, n=8 animals/group. After euthanasia, blood and liver were collected and analyzed. The hematimetric indices provided no significant differences between the control and experimental. Moreover, doxycycline did not interfere with the immune system, once the leukogram was similar between the two groups. Levels of urea and creatinine were also similar comparing the control and the experimental group. Doxycycline did not damage the livers’architecture, and aspartate and alanine aminotransferases presented typical activities. Regarding oxidative stress, the GSH-Px enzyme was the only parameter that presented an increase in the experimental group compared to the control. In conclusion, doxycycline proved to be a safe drug in long-term administration. The increase in the GSH-Px activity could be related to an increase in selenocysteine insertion induced by doxycycline, activating the enzyme.