Dataset Information

Galantamine prevents and reverses neuroimmune induction and loss of adult hippocampal neurogenesis following adolescent alcohol exposure.

ABSTRACT:

Background

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. 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.

Methods

Galantamine (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).

Results

Results 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 (gp91^phox).

Conclusions

Collectively, 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.

SUBMITTER: Macht V

PROVIDER: S-EPMC8447570 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alcohol abuse and binge drinking are common during adolescence, a developmental period characterized by heightened neuroplasticity. Animal studies reveal that adolescent ethanol exposure decreases hippocampal neurogenesis that persists into adulthood, but the mechanism remains to be fully elucidated. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-days on/2-days off from postnatal day [P]25 to P55), we tested the hypothesis that AIE-induced upregulation of neuroimmune signaling contributes to the loss of hippocampal neurogenesis in adulthood. We found that AIE caused upregulation of multiple proinflammatory Toll-like receptors (TLRs), increased expression of phosphorylated NF-?B p65 (pNF-?B p65) and the cell death marker cleaved caspase 3, and reduced markers of neurogenesis in the adult (P80) hippocampus, which is consistent with persistently increased neuroimmune signaling reducing neurogenesis. We observed a similar increase of pNF-?B p65-immunoreactive cells in the post-mortem human alcoholic hippocampus, an effect that was negatively correlated with age of drinking onset. Voluntary wheel running from P24 to P80 prevented the AIE-induced loss of neurogenesis markers (i.e., nestin and doublecortin) in the adult hippocampus that was paralleled by blockade of increased expression of the cell death marker cleaved caspase 3. Wheel running also prevented the AIE-induced increase of hippocampal pNF-?B p65 and induction of neuroimmune NF-?B target genes, including TNF? and I?B? in the adult brain. Administration of the anti-inflammatory drug indomethacin during AIE prevented the loss of neurogenesis markers (i.e., nestin and doublecortin) and the concomitant increase of cleaved caspase 3, an effect that was accompanied by blockade of the increase of pNF-?B p65. Similarly, administration of the proinflammatory TLR4 activator lipopolysaccharide resulted in a loss of doublecortin that was paralleled by increased expression of cleaved caspase 3 and pNF-?B p65 in the hippocampal dentate gyrus of CON animals that mimicked the AIE-induced loss of neurogenesis. Taken together, these data suggest that exercise and anti-inflammatory drugs protect against adolescent binge ethanol-induced brain neuroimmune signaling and the loss of neurogenesis in the adult hippocampus.