Salmeterol, a β2 Adrenergic Agonist, Promotes Adult Hippocampal Neurogenesis in a Region-Specific Manner

Abstract

Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (β-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of β2-AR by norepinephrine and β2-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective β2-AR agonist able to cross the blood–brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult naïve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior.

Short high fat diet triggers reversible and region specific effects in DCX+ hippocampal immature neurons of adolescent male mice

“…Conversely, adult‐born neurons in the ventral, but not dorsal, DG are negatively affected by chronic stress 58 . Last but no least several clinically relevant drugs, including antidepressants, specifically promote hNG in ventral hippocampus 15 , 27 , 58 . The finding that, in our experimental setting, we observed structural modifications of DCX + cells selectively in the dorsal hippocampus could potentially infer that a short period of high-caloric nutrition may preferentially affect hippocampal- and neurogenesis-dependent functions, including cognition.…”

Astrocyte-Derived Paracrine Signals: Relevance for Neurogenic Niche Regulation and Blood–Brain Barrier Integrity

“…The α2δ1 subunit was also proven to be functionally expressed by adult hippocampal NPC and to mediate TSP-1 and pregabalin (an anticonvulsant/analgesic α2δ1 ligand) pro-neurogenic effects both in vitro and in vivo (Valente et al, 2012). These findings were further extended in recent studies proposing a key role for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling whose activation occurs in adult NSC via membrane receptors, including neurotransmitter receptors and α2δ1 (Meneghini et al, 2010; Bortolotto et al, 2017a; Bortolotto et al, 2019). NF-κB p50 −/− mice exhibit strongly reduced ahNG in vivo (Denis-Donini et al, 2008) and in vitro (Meneghini et al, 2013; Valente et al, 2015; Bonini et al, 2016).…”

Assessing the Possible Influence of Residues of Ractopamine, a Livestock Feed Additive, in Meat on Alzheimer Disease

“…Contrary to what has been mentioned above, activation of the β 2 -adrenoreceptor by the β 2 -adrenergic agonist clenbuterol in transgenic mice carrying chimeric mouse/human AβPP and mutant human presenilin 1, an Alz­heimer disease animal model, significantly stimulated hippocampal neurogenesis and reversed memory deficits [17]. Another selective β 2 -adrenergic agonist, i.e., salmeterol, when chronically administrated in mice, exerts a prosurvival effect of neuroblasts and beneficially modulates hippocampal neuroplasticity [18]. Accordingly, ractopamine residue in meat probably would improve symptoms of dementia in Alzheimer disease rather than worsen them.…”