A Novel Effect of Bifemelane, a Nootropic Drug, on Intracellular Ca2+ Levels in Rat Cerebral Astrocytes

Abstract

Abstract. We investigated the effects of bifemelane, a nootropic drug, on the intracellular calcium concentration ([Ca 2+ ] i ) in rat cerebral astrocytes using a Ca 2+ imaging device. At concentrations of 10 -30 µM, bifemelane induced a slow onset and small increase in the [Ca 2+] i , while at higher concentrations (100 -300 µM), it induced a rapid transient increase in the [Ca 2+] i during administration and a second large increase was seen during drug washout. The first peak was observed in Ca 2+ -free medium, but its onset was significantly delayed, and no second peak was seen. Neither of these effects was seen in cells treated with thapsigargin, a specific inhibitor of endoplasmic reticulum Ca 2+-ATPase, in Ca 2+ -free medium. When thapsigargintreated astrocytes were returned to normal medium containing Ca 2+ (1.8 mM), the [Ca 2+ ] i increased significantly, and this effect was reversely inhibited by bifemelane. We conclude that bifemelane causes the first peak by stimulating release from intracellular Ca 2+ stores and the second by capacitive entry through store-operated Ca 2+ channels. Although the detail mechanisms of action of the drug are still unknown, bifemelane will be provided as a pharmacological tool for basic studies on astrocytes.

Effects of Bifemelane on the Calcium Level and ATP Release of the Human Origin Astrocyte Clonal Cell

“…] i were almost the same as those found in rat astrocytes (5). The effects of bifemelane were dose-dependent.…”

“…-free medium and could be induced by exchanging the washing medium with normal Ca 2+ medium, it can be estimated that Ca 2+ entered the cells through storeoperated Ca 2+ channels (5,13). Since our data demonstrated that carbachol and histamine, which caused a strong increase in [Ca 2+ ] i , had no effects on the ATP release, the increase in [Ca 2+ ] i level did not always participate in ATP release from astrocytes.…”

“…At higher concentrations, the drug facilitated Ca 2+ influx from the extracellular space through the store operated Ca 2+ channels (SOCC) during washing. Interestingly, the drug induced rapid onset and highly reversible blocking effects on the SOCC activated in the cells treated with thapsigargin and bathed in normal medium (5). Although the dose required to cause the effect seemed to be much higher than its therapeutic dose, the effects of bifemelane on the [Ca 2+ ] i of astrocytes found in our previous study might have some relationship to the pharmacological and therapeutic efficiency of the drug (6,7).…”

“…In our previous paper on the cultured rat cerebral astrocytes, we found that bifemelane hydrochloride (bifemelane), which had been developed as a nootropic drug, induced a characteristic increase in the intracellular calcium concentration ([Ca 2+ ] i ), from intracellular storage sites (5). At higher concentrations, the drug facilitated Ca 2+ influx from the extracellular space through the store operated Ca 2+ channels (SOCC) during washing.…”