Novel GLP‐1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain

Abstract

One of the symptoms of diabetes is the progressive development of neuropathies. One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells. We have tested the effects of the novel GLP-1 mimetics exenatide (exendin-4; Byetta) and liraglutide (NN2211; Victoza), which are already on the market as treatments for type 2 diabetes, on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes. GLP-1 analogues were injected subcutaneously for 4, 6, or 10 weeks once daily in three mouse models of diabetes: ob/ob mice, db/db mice, or high-fat-diet-fed mice. Twenty-four hours before perfusion, animals were injected with 5'-bromo-2'-deoxyuridine (BrdU) to mark dividing progenitor cells. By using immunohistochemistry and stereological methods, the number of progenitor cells or doublecortin-positive young neurons in the dentate gyrus was estimated. We found that, in all three mouse models, progenitor cell division was enhanced compared with nondiabetic controls after chronic i.p. injection of either liraglutide or exendin-4 by 100-150% (P < 0.001). We also found an increase in young neurons in the DG of high-fat-diet-fed mice after drug treatment (P < 0.001). The GLP-1 receptor antagonist exendin(9-36) reduced progenitor cell proliferation in these mice. The results demonstrate that GLP-1 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer's disease, because these novel drugs cross the blood-brain barrier and increase neuroneogenesis.

Hormonal Signaling Systems of the Brain in Diabetes Mellitus

“…Note that Liraglutide, analog of human GLP-1 with prolonged half life having a fatty acid palmitoyl group conjugated to the side-chain of Lys 26 and an Arg 34 Ser substitution, is now widely used in DM2 therapy (Lovshin, Drucker, 2009). Exendin-4 and Liraglutide injected subcutaneously for 4, 6, or 10 weeks once daily in ob/ob, db/db and high-fat-diet-fed mice enhanced proliferation rate of progenitor cells by 100-150 % and stimulated differentiation into neurons in the dentate gyrus (Hamilton et al, 2011). The GLP-1 receptor antagonist exendin(9-36) significantly reduced progenitor cell proliferation in these mice.…”

“…GLP-1 is effective in restoring first-phase insulin response and lowering hyperglycemia in DM2 (Doyle & Egan, 2007). GLP1 also functions in the brain as a neurotransmitter, has the growth factor-like properties and protects neurons from neurotoxic influence, controlling learning behavior, memory and synaptic plasticity (Hamilton & Holscher, 2009;Hamilton et al, 2011). The action of GLP-1 is realized via GLP-1 receptors that in the brain affect neuronal activity through regulation of intracellular cAMP-dependent pathways, modulation of Ca 2+ channels, activation of ERK1/ERK2 kinases and other second messenger systems involved in transmitter vesicle release (Gilman et al, 2003) (Fig.…”

A Novel GLP1 Receptor Interacting Protein ATP6ap2 Regulates Insulin Secretion in Pancreatic Beta Cells

“…Further, GLP1 or its analogs were shown to lower blood pressure in rodents and human subjects (12)(13)(14). In the brain, GLP1 analogs induced the proliferation of neuronal progenitor cells, implicating a potential involvement in the repair of neurons (15)(16)(17).…”

The Effects of Glucagon Like Peptid-1 on Nervous System and Appetite

“…Bu yararlı etkiler serbest oksijen radikallerinin azaltılması ve PI3K/Akt ve MAPK yolu ile ortaya çıktığı bildirilmektedir (21). Ob/ob, db/db farelerde ve yüksek yağ ile beslenen farelerde dentat girusdaki projentör hücre çoğalmasını artırarak nörogenezisi sağladığı gösterilmiştir (22) Parkinson hastalığının deneysel modellerinde ise eksendin-4 uygulamasının nörogenezisi, substantia nigradaki dopaminerjik nöron miktarını artırdığı gösterilmiştir (23). Bu koruyucu etkilerden dolayı ekstendin-4'ün PD'da kullanımı ile klinik çalışmalar başlamıştır.…”