Матер. III съезда фармакологов России, 23-27 сентября 2007 г. (Тез 533)

Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. Mitochndria-regulating effects of mildronate in azidothymidine-induced toxicity Proceedings of the III Congress of Pharmacology Russia, Saint-Petersburg, 23–27 September 2007. Abstr 533. Psychopharmacol Biol Narcol 2007 Sept; 7 Suppl (Pt 2, M–Ja): 2-1911–2-1911 [in English]AZT (azidothymidine) is the first antiMHIV drug used in AIDS treatment, and it is still most commonly used in drug combinations. AZT inhibits polymerase g which is responsible for HIVM1 mitochondrial DNA replication, changes the structure of mitochondria by its incorporation into mitochondria [Peters et al., 1993]. Therefore the use of AZT is limited due to its severe side effects — myopathies, especially cardiomyopathies, lipodystrophy, hepatic steatosis, lactic acidosis and others [Badley et al., 2003]. We have suggested that AZTMinduced toxicity may be prevented by drugs capable of regulating mitochondrial processes. Hence, we have used mildronate, a cardioprotective drug of azaMbutyrobetaine class, which was shown to protect rat heart mitochondria from free fatty acid detergentMlike action by inhibiting carnitine palmitoyl transferase 1 [Dambrova et al., 2002]. Besides, mildronate protects the energy metabolism against the H2O2Minduced derangement in isolated rat heart (Akahira et al., 1997) and improves cardiac sarcoplasmic reticulum Ca2+ uptake activity [Hayashi et al., 2000]. In the present study, AZT and mildronate were administered in male mice intraperitoneally, per se and in combinations during a twoMweek period at doses previously found as the most active ones: AZT 50 mg/kg, and mildronate 50, 100 and 200 mg/kg. After termination of drug administration, mice were sacrificed and their heart and brain tissue were removed. Immunohistochemical assessment of nuclear factor kappa B (NFMkBp65) in the heart, and morphological assessment of heart and brain tissue was performed. The obtained results showed that AZT treatment significantly increased NFMkBp65 expression, indicating manifestation of oxidative stress leading to mitochondrial damage. AZT caused also morphological — inflammatory and degenerative — alterations in mice heart tissue. In brain tissue AZT caused degeneration of neurons in the molecular layer and external granular layer. Mildronate in combination with AZT reduce these AZTMinduced pathologic actions both in heart and brain tissue, demonstrating its powerful protective action. One may suggest that mildronate’s protective activity is provided via targeting mitochondrial processes. That indicates usefulness of mildronate’s combination with antiMHIV and other mitochondriaMcompromized drugs.  Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. . Матер. III съезда фармакологов России. Психофармакол биол наркол 2007 Спец Вып; 7 (Ч 2, М–Я): 2-1911–2-1911 (Тез 533

Матер. III съезда фармакологов России, 23-27 сентября 2007 г. (Тез 533)

Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. Mitochndria-regulating effects of mildronate in azidothymidine-induced toxicity Proceedings of the III Congress of Pharmacology Russia, Saint-Petersburg, 23–27 September 2007. Abstr 533. Psychopharmacol Biol Narcol 2007 Sept; 7 Suppl (Pt 2, M–Ja): 2-1911–2-1911 [in English]AZT (azidothymidine) is the first antiMHIV drug used in AIDS treatment, and it is still most commonly used in drug combinations. AZT inhibits polymerase g which is responsible for HIVM1 mitochondrial DNA replication, changes the structure of mitochondria by its incorporation into mitochondria [Peters et al., 1993]. Therefore the use of AZT is limited due to its severe side effects — myopathies, especially cardiomyopathies, lipodystrophy, hepatic steatosis, lactic acidosis and others [Badley et al., 2003]. We have suggested that AZTMinduced toxicity may be prevented by drugs capable of regulating mitochondrial processes. Hence, we have used mildronate, a cardioprotective drug of azaMbutyrobetaine class, which was shown to protect rat heart mitochondria from free fatty acid detergentMlike action by inhibiting carnitine palmitoyl transferase 1 [Dambrova et al., 2002]. Besides, mildronate protects the energy metabolism against the H2O2Minduced derangement in isolated rat heart (Akahira et al., 1997) and improves cardiac sarcoplasmic reticulum Ca2+ uptake activity [Hayashi et al., 2000]. In the present study, AZT and mildronate were administered in male mice intraperitoneally, per se and in combinations during a twoMweek period at doses previously found as the most active ones: AZT 50 mg/kg, and mildronate 50, 100 and 200 mg/kg. After termination of drug administration, mice were sacrificed and their heart and brain tissue were removed. Immunohistochemical assessment of nuclear factor kappa B (NFMkBp65) in the heart, and morphological assessment of heart and brain tissue was performed. The obtained results showed that AZT treatment significantly increased NFMkBp65 expression, indicating manifestation of oxidative stress leading to mitochondrial damage. AZT caused also morphological — inflammatory and degenerative — alterations in mice heart tissue. In brain tissue AZT caused degeneration of neurons in the molecular layer and external granular layer. Mildronate in combination with AZT reduce these AZTMinduced pathologic actions both in heart and brain tissue, demonstrating its powerful protective action. One may suggest that mildronate’s protective activity is provided via targeting mitochondrial processes. That indicates usefulness of mildronate’s combination with antiMHIV and other mitochondriaMcompromized drugs.  Pupure J., Fernandes M.A.S., Oliveira C.R., Moreno A.J.M., Santos M.S., Kalvinsh I., Isajevs S., Klusa V. . Матер. III съезда фармакологов России. Психофармакол биол наркол 2007 Спец Вып; 7 (Ч 2, М–Я): 2-1911–2-1911 (Тез 533