» Articles » PMID: 23173075

Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo

Overview
Specialty Neurology
Date 2012 Nov 23
PMID 23173075
Citations 69
Authors
Affiliations
Soon will be listed here.
Abstract

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic drugs in neuroregenerative medicine.

Citing Articles

Advancements in PROTAC-based therapies for neurodegenerative diseases.

Kong D, Meng L, Lin P, Wu G Future Med Chem. 2025; 17(5):591-605.

PMID: 39931801 PMC: 11901405. DOI: 10.1080/17568919.2025.2463310.


Natural products against tau hyperphosphorylation-induced aggregates: Potential therapies for Alzheimer's disease.

Basurto-Islas G, Diaz M, Ocampo L, Martinez-Herrera M, Lopez-Camacho P Arch Pharm (Weinheim). 2025; 358(1):e2400721.

PMID: 39888017 PMC: 11781347. DOI: 10.1002/ardp.202400721.


GSK3: A potential target and pending issues for treatment of Alzheimer's disease.

Zhao J, Wei M, Guo M, Wang M, Niu H, Xu T CNS Neurosci Ther. 2024; 30(7):e14818.

PMID: 38946682 PMC: 11215492. DOI: 10.1111/cns.14818.


Design, Synthesis, and Biological Evaluation of Novel Tetrahydroacridin Hybrids with Sulfur-Inserted Linkers as Potential Multitarget Agents for Alzheimer's Disease.

Wu X, Ze X, Qin S, Zhang B, Li X, Gong Q Molecules. 2024; 29(8).

PMID: 38675602 PMC: 11051924. DOI: 10.3390/molecules29081782.


Gens PSD-95 and GSK-3β expression improved by hair follicular stem cells-conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia.

Ghobadi M, Akbari S, Bayat M, Shid Moosavi S, Salehi M, Pandamooz S Brain Behav. 2024; 14(1):e3351.

PMID: 38376050 PMC: 10757903. DOI: 10.1002/brb3.3351.


References
1.
Palomo V, Perez D, Perez C, Morales-Garcia J, Soteras I, Alonso-Gil S . 5-imino-1,2,4-thiadiazoles: first small molecules as substrate competitive inhibitors of glycogen synthase kinase 3. J Med Chem. 2012; 55(4):1645-61. DOI: 10.1021/jm201463v. View

2.
Biscaro B, Lindvall O, Hock C, Ekdahl C, Nitsch R . Abeta immunotherapy protects morphology and survival of adult-born neurons in doubly transgenic APP/PS1 mice. J Neurosci. 2009; 29(45):14108-19. PMC: 6665051. DOI: 10.1523/JNEUROSCI.2055-09.2009. View

3.
Bonfanti L, Olive S, Poulain D, Theodosis D . Mapping of the distribution of polysialylated neural cell adhesion molecule throughout the central nervous system of the adult rat: an immunohistochemical study. Neuroscience. 1992; 49(2):419-36. DOI: 10.1016/0306-4522(92)90107-d. View

4.
Martinez A, Castro A, Dorronsoro I, Alonso M . Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev. 2002; 22(4):373-84. DOI: 10.1002/med.10011. View

5.
Toni N, Teng E, Bushong E, Aimone J, Zhao C, Consiglio A . Synapse formation on neurons born in the adult hippocampus. Nat Neurosci. 2007; 10(6):727-34. DOI: 10.1038/nn1908. View