3,3'-Diindolylmethane attenuates recognition memory impairment induced by binge ethanol exposure in mice

Binge drinking, defined as excessive alcohol consumption over a short period, is most common at ages that are particularly vulnerable to the harmful effects of alcohol. Cognitive functions are severely affected, and there is a concern that the consequences of alcohol consumption in early life stages can perpetuate into adulthood. 3,3'-Diindolylmethane (DIM) has recently been found to have neuroprotective activity. We aimed to investigate whether DIM could mitigate binge ethanol-induced memory deficits, and to explore the underlying mechanisms. Mice underwent four binge episodes spaced five days apart. Each episode consisted of three intraperitoneal ethanol injections (2.5, 2.5 and 2 g/kg) given at two-hour intervals. DIM (50 mg/kg/day, i.p) was administered during the last four days of the protocol, with the final dose being given 30 min prior to the first ethanol injection of the last binge episode. DIM attenuates the object recognition memory deficit induced by ethanol 20 h after the last exposure, an effect that can be sustained until 7 days if dosing is continued until testing. DIM increases the expression of the glutamate transporter EAAT2 and reduces the ethanol-induced disruption of the GluN2A/GluN2B receptor ratio but does not alter the ethanol-induced increase in AMPA receptor membrane trafficking. DIM reduces the ethanol induced-increase in MMP-9 activity and facilitates the survival of immature neurons without modifying the ethanol-induced decrease in mature neurons nor the increase in microglia. DIM may be a promising therapeutic candidate for ethanol-induced memory deficits through modulation of glutamatergic neurotransmission, hippocampal neurogenesis and MMP-9 activity.