Abstract
BackgroundBinge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. As galantamine, a cholinesterase inhibitor, has anti-inflammatory actions, we tested the hypothesis that galantamine would prevent (study 1) or restore (study 2) AIE induction of proinflammatory signals within the hippocampus as well as AIE-induced loss of hippocampal neurogenesis.MethodsGalantamine (4 mg/kg) or vehicle (saline) was administered to Wistar rats during adolescent intermittent ethanol (AIE; 5.0 g/kg ethanol, 2 days on/2 days off, postnatal day [P] 25-54) (study 1, prevention) or after AIE during abstinent maturation to adulthood (study 2, restoration).ResultsResults indicate AIE reduced DCX+IR and induced cleaved caspase3 (Casp3) in DCX-expressing immature neurons. Excitingly, AIE induction of activated Casp3 in DCX-expressing neurons is both prevented and reversed by galantamine treatment, which also resulted in prevention and restoration of neurogenesis (DCX+IR). Similarly, galantamine prevented and/or reversed AIE induction of proinflammatory markers, including the chemokine (C-C motif) ligand 2 (CCL2), cyclooxygenase-2 (COX-2), and high mobility group box 1 (HMGB1) protein, suggesting that AIE induction of proinflammatory signaling mediates both cell death cascades and hippocampal neurogenesis. Interestingly, galantamine treatment increased Ki67+IR generally as well as increased pan-Trk expression specifically in AIE-treated rats but failed to reverse AIE induction of NADPH-oxidase (gp91phox).ConclusionsCollectively, our studies suggest that (1) loss of neurogenesis after AIE is mediated by persistent induction of proinflammatory cascades which drive activation of cell death machinery in immature neurons, and (2) galantamine can prevent and restore AIE disruptions in the hippocampal environmental milieu to then prevent and restore AIE-mediated loss of neurogenesis.
Highlights
Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence
Galantamine significantly increased DCX+IR by 43% within adolescent intermittent ethanol (AIE)-exposed rats, p < 0.001 (Fig. 2, Table 4). These results indicate that galantamine pretreatment can prevent AIE-induced deficits in hippocampal neurogenesis
Chemokine ligand 2 (CCL2) is a chemokine that can function as a neuromodulator to impact neuronal excitability and impair neurogenesis. (A) The current study found that galantamine blocked AIE induction of CCL2 in the hilus, suggesting that increasing acetylcholine signaling combats ethanol-induced proinflammatory cascades. (B) Example photomicrographs taken at 20× magnification of each group: CON-Veh, CON-Gal, AIE-Veh, AIE-Gal
Summary
Binge ethanol exposure during adolescence reduces hippocampal neurogenesis, a reduction which persists throughout adulthood despite abstinence. This loss of neurogenesis, indicated by reduced doublecortin+ immunoreactivity (DCX+IR), is paralleled by an increase in hippocampal proinflammatory signaling cascades. It is becoming increasingly appreciated that neurogenic disruptions during adolescence (e.g., binge ethanol exposure) persist throughout adulthood [3] and are driven by upregulation of proinflammatory factors paralleled by a loss of trophic support (for review see [2]) as well as dysregulation of cholinergic anti-inflammatory networks [4, 5]. The current study used doublecortin (DCX), which marks immature neurons, to examine the effects of adolescent ethanol exposure on hippocampal neurogenesis rather than gliogenesis
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