Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis - PubMed (original) (raw)

Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis

Kerry Hunter et al. BMC Neurosci. 2012.

Abstract

Background: Type 2 diabetes is a risk factor for Alzheimer's disease (AD), most likely linked to an impairment of insulin signalling in the brain. Therefore, drugs that enhance insulin signalling may have therapeutic potential for AD. Liraglutide (Victoza) and exenatide (Byetta) are novel long-lasting analogues of the GLP-1 incretin hormone and are currently available to treat diabetes. They facilitate insulin signalling via the GLP-1 receptor (GLP-1R). Numerous in vitro and in vivo studies have shown that GLP-1 analogues have a range of neuroprotective properties. GLP-1Rs are expressed in the hippocampal area of the brain an important site of adult neurogenesis and maintenance of cognition and memory formation. Therefore, if GLP-1 analogues can cross the blood brain barrier, diffuse through the brain to reach the receptors and most importantly activate them, their neuroprotective effects may be realized.

Results: In the present study we profiled the GLP-1 receptor agonists liraglutide (Victoza) and lixisenatide (Lyxumia). We measured the kinetics of crossing the blood brain barrier (BBB), activation of the GLP-1R by measuring cAMP levels, and physiological effects in the brain on neuronal stem cell proliferation and neurogenesis. Both drugs were able to cross the BBB. Lixisenatide crossed the BBB at all doses tested (2.5, 25, or 250 nmol/kg bw ip.) when measured 30 min post-injection and at 2.5-25 nmol/kg bw ip. 3 h post-injection. Lixisenatide also enhanced neurogenesis in the brain. Liraglutide crossed the BBB at 25 and 250 nmol/kg ip. but no increase was detectable at 2.5 nmol/kg ip. 30 min post-injection, and at 250 nmol/kg ip. at 3 h post-injection. Liraglutide and lixisenatide enhanced cAMP levels in the brain, with lixisenatide being more effective.

Conclusions: Our results suggest that these novel incretin analogues cross the BBB and show physiological activity and neurogenesis in the brain, which may be of use as a treatment of neurodegenerative diseases.

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Figures

Figure 1

Figure 1

At 5 min post- ip. injection, there was no significant increase of liraglutide in the brains of mice (A). There was an increase in liraglutide levels in the brains of mice injected with 25 or 250 nmol/kg bw at 30 min (B) and only those injected with the highest dose at 3 h post-injection (C). Brain levels of cAMP were increased 30 min post injection with 25 nmol/kg bw ip.. * = p < 0.05. Values are the mean ± S.E.M.

Figure 2

Figure 2

(A) Lixisenatide levels in the brains at 30 min following i.p. (2.5, 25 or 250 nmol/kg body weight) injection were increased. (B) Lixisenatide levels in the brains at 3 h following i.p. injection were only increased for the lower doses (2.5, 25 nmol/kg body weight). (C) The number of neuronal progenitor cells in the dentate gyrus was increased after 3 weeks of ip injection 25 nmol/kg bw once-daily. (D) The number of young neurons in the dentate gyrus was also increased. (E) The level of cAMP was enhanced in the brains after injection with 25 nmol/kg bw ip. (F) When directly comparing the effects of liraglutide with lixisenatide, a significant difference between drugs is found.* = p < 0.05, ** = p < 0.01. Micrographs: BrdU stain: A Saline control B Lixisenatide treated, 3 weeks once daily i.p. injection. Blue arrows point to BrdU positively stained cells. DCX stain: Doublecortin stained immature neurons in dentate gyrus. A Saline control B Lixisenatide treated, 3 weeks once daily i.p. administration.

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