Effects of ranolazine on astrocytes and neurons in primary culture

Ranolazine (Rn) is an antianginal agent used for the treatment of chronic angina pectoris when angina is not adequately controlled by other drugs. Rn also acts in the central nervous system and it has been proposed for the treatment of pain and epileptic disorders. Under the hypothesis that ranolazine could act as a neuroprotective drug, we studied its effects on astrocytes and neurons in primary culture. We incubated rat astrocytes and neurons in primary cultures for 24 hours with Rn (10−7, 10−6 and 10−5 M). Cell viability and proliferation were measured using trypan blue exclusion assay, MTT conversion assay and LDH release assay. Apoptosis was determined by Caspase 3 activity assay. The effects of Rn on proinflammatory mediators IL-β and TNF-α was determined by ELISA technique, and protein expression levels of Smac/Diablo, PPAR-γ, Mn-SOD and Cu/Zn-SOD by western blot technique. In cultured astrocytes, Rn significantly increased cell viability and proliferation at any concentration tested, and decreased LDH leakage, Smac/Diablo expression and Caspase 3 activity indicating less cell death. Rn also increased anti-inflammatory PPAR-γ protein expression and reduced pro-inflammatory proteins IL-1 β and TNFα levels. Furthermore, antioxidant proteins Cu/Zn-SOD and Mn-SOD significantly increased after Rn addition in cultured astrocytes. Conversely, Rn did not exert any effect on cultured neurons. In conclusion, Rn could act as a neuroprotective drug in the central nervous system by promoting astrocyte viability, preventing necrosis and apoptosis, inhibiting inflammatory phenomena and inducing anti-inflammatory and antioxidant agents

CARDIOPROTECTION BY PRE- AND POST-CONDITIONING: IMPLICATIONS FOR THE ROLE OF MITOCHONDRIA

The mitochondrion has evolved as an important organelle in determining cell survival and cell death. It is involved in a plethora of processes in mammalian cells including ATP production, steroid synthesis, and cell division and cell death. Indeed, mitochondrial dysfunction is associated with numerous human maladies including heart disease. Mitochondrial diseases have traditionally been attributed to defects in the electron transport chain (ETC), the major source of mitochondrial reactive oxygen species (ROS), a byproduct of mitochondrial respiration. Mitochondrial cation channels and exchangers function to maintain matrix homeostasis and are likely involved in modulating mitochondrial function in part by regulating O2 •- generation. Insofar as mitochondria are involved in oxidative damage that leads to apoptosis, antioxidants and other therapeutic strategies that target the organelle appear to be a novel approach to alleviate some cardiovascular diseases. This novel approach has gained unprecedented attention recently with a significant potential for future therapeutic purpose. Whether mitochondria are targets or end effectors of cardiac pre- and post-conditioning remain unresolved. This brief review will provide the latest information gleaned from the literature on the role of mitochondria in pre- and post-conditioning during cardiac ischemia and reperfusion