Neurotrophic property of geniposide for inducing the neuronal differentiation of PC12 cells

Liu, J. et al.
Chongqing Technology and Business University, Chongqing , China
Int. J. Devl Neuroscience
Nov. 2006 [Pubmed]

This paper discusses the use of a cell-based assay to identify geniposide as a potential agonist of Glp1r and then establishes that geniposide can induce neurite outgrowth in a culture. The supposed Glp1r-screening assay seems to be very nonspecific. It is a luciferase reporter gene hooked up to a series of CREB response elements (CRE) so anything that induces CREB (which is many, many things) will generate a positive in the screen. The only indication that geniposide is acting through Glp1r is data from cell lines with and without the overexpression of Glp1r. Overexpression of Glp1r greatly increases the response of the reporter construct. This does not indicate that geniposide is specific for Glp1r. The authors tested cell lines overexpressing a serotonin and dopamine receptor and showed no increase in response but there are still many other more closely related receptors that geniposide could be acting through. The data from the neurite outgrowth is somewhat obvious. It is clear by the cell-based assay that geniposide activates the CREB pathway and it is already known that CREB pathway activities increases neurite outgrowth. The real question that remains and the critical one going forward is whether geniposide is a specific agonist of Glp1r. If you were to administer geniposide to an animal, will it only have the effect of other Glp1r agonists or will it have a number of unexpected consequences and side effects due to off target activity? This paper does not provide any guidance in this area. In fact, there are no papers other than this one even linking geniposide with the Glp1 pathway. Additionally, in the 100 some papers discussing geniposide, none of them link it to many of the hallmarks of Glp1 action link insulin response. This paper stands alone in providing this link.

Some other notes;

GLP1 is produced predominantly in the intestines.

GLP1R has been shown to be expressed in the brains of both humans and rodents including hypothalamus, thalamus, brainstem, lateral septum, subfornical organ.

GLP1R activation has been shown to induce neurite outgrowth by cyclic AMP signaling.

GLP1 and extendin-4 have been shown to have neuroprotective properties.

GLP1 and extendin-4 reduces A Beta when infused into the lateral ventricles.

In a well established rodent model of cholinergic neurodegeneration, infusion of GLP-1 had shown complete amelioration of an ibotenic acid-induced cholinergic marker deficit.

Geniposide has been shown to protect against neuronal cell death.