α7 nicotinic receptor agonist reactivates neurogenesis in adult brain.
Reactivation of neurogenesis by endogenous Neural Stem/Progenitor Cells (NS/PC) in the adult brain or spinal cord holds the key for treatment of CNS injuries as well as neurodegenerative disorders, which are major healthcare issues for the world's aging population. Recent studies show that targeting the α7 nicotinic acetylcholine receptors (α7nAChR) with a specific TC-7020 agonist inhibits proliferation and stimulates neuronal differentiation of NS/PC in subventricular zone (SVZ) in the adult mouse brain. TC-7020-induced neuronogenesis is observed in different brain regions, including: (1) βIII Tubulin-expressing cortical neurons, (2) calretinin expressing hippocampal neurons and (3) cells in substantia nigra (SN) expressing predopaminergic Nurr1+phenotype. Reactivation of developmental integrative nuclear FGFR1 signaling (INFS), via gene transfection reinstates neurogenesis in the adult brain by promoting neuronal differentiation of brain NS/PC. TC-7020 neuronogenic effect is associated with a robust accumulation of endogenous FGFR1 in the nuclei of differentiating cells. Furthermore, direct in vitro stimulation of neural stem/progenitor cells with α7nAChR agonist activates INFS and neuronal-like differentiation and activation of neuronal genes. The α7nAChR upregulation of early neuronal βIII-Tubulin gene involves neurogenic FGFR1-Nur signaling and direct FGFR1 interaction with the gene promoter. The reactivation of developmental INFS and neurogenesis in adult brain by the α7nAChR agonist may offer new strategy to treat brain injuries, neurodegenerative and neurodevelopmental diseases.
Department of Pathology and Anatomical Sciences, State University of New York at Buffalo, Buffalo, NY, USA.
Sridhar
S
Narla
Ilona
I
Klejbor
Barbara
B
Birkaya
Yu-Wei
YW
Lee
Janusz
J
Morys
Ewa K
EK
Stachowiak
Christopher
C
Terranova
Merouane
M
Bencherif
Michal K
MK
Stachowiak
D000818:Animals; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011812:Quinuclidines / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism*
C573434:5-methyl-N-(2-(pyridin-3-ylmethyl)-1-azabicyclo(2.2.2)oct-3-yl)thiophene-2-carboxamide; D018722:Nicotinic Agonists; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor
Brain; Neurogenesis; Nicotinic receptors; Nuclear FGF receptor; Stem cells