Ranolazine alleviated cardiac/brain dysfunction in doxorubicin-treated rats

Abstract

Doxorubicin (Dox), a powerful chemotherapeutic agent, has been shown to cause cardiotoxicity and neurotoxicity. Ranolazine, a drug that is commonly used to treat patients with chronic angina, has been shown to reduce toxicity from Dox therapy. Therefore, the present study aims to investigate the mechanisms behind the protective effects of ranolazine on the heart and brain in Dox-treatment. Twenty-four male Wistar rats received 6 doses of either 0.9% normal saline (0.9% NSS, i.p., n = 8) or Dox (3 mg/kg, i.p., n = 16). All Dox-treated rats were assigned into 2 groups to receive vehicle (0.9% NSS, orally; n = 8) or ranolazine (305 mg/kg/day, orally; n = 8) for 30 consecutive days. Following the treatments, left ventricular (LV) function and cognition were determined. Animals were euthanized, then the heart and brain were collected for further analysis. Dox induced systemic oxidative stress/inflammation, and cardiac injury evidenced by mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis, resulting in LV dysfunction. Ranolazine significantly improved LV function via attenuating cardiac injury. Dox also caused brain pathologies as indicated by increased brain inflammation, impaired blood-brain barrier integrity, brain mitochondrial dysfunction, microglial dysmorphology, hippocampal dysplasticity, and increased apoptosis, resulting in cognitive decline. Ranolazine exerted neuroprotective effects by suppressing brain pathologies and restoring cognitive function. These findings suggest that ranolazine has a potential role in cardio- and neuro-protection against chemotherapy.