More research to follow up on.
http://www.biomedcentral.com/content/pdf/1471-2202-13-33.pdf
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.
Background
Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance resulting in glucose
intolerance and hyperglycaemia [1].
Since insulin effectiveness is reduced in diabetes, research into other signalling pathways that
support insulin actions or that reduce blood glucose is ongoing. One of these strategies focus
on the use of the incretins, a class of peptide hormones that helps to normalise insulin
signaling and also improves blood sugar levels. Incretins increase the release of insulin
during high blood sugar levels, the so-called ‘incretin effect’. Drugs that mimic incretin
hormones can maintain glucose homeostasis and improve multiple symptoms of type 2
diabetes like the risk of hypoglycaemia, inadequate post-prandial blood glucose control,
glucose fluctuations, β-cell failure, and weight gain [1,2].
GLP-1 is an endogenous 30-amino acid peptide hormone. Numerous novel long-lasting GLP-
1 receptor agonists have been developed by several companies. Exendin-4 (Byetta) has been
on the market as a T2DM treatment for several years [3]. Liraglutide (Victoza) also has been
released onto the market several years ago [4]. A third drug is lixisenatide (Lyxumia), which
will be released onto the market soon [5].
T2DM has been identified as a risk factor for AD, indicating that insulin signaling failure
may be a factor in initiating or accelerating the development of AD. Epidemiological studies
found a clear correlation between T2DM and the risk of developing AD [6-8]. It was also
shown that insulin receptors in the brain are desensitised in AD patients [9,10]. Therefore, a
promising strategy to treat AD is the use of such GLP-1 analogues [11]. GLP-1 receptors are
found on neurons in the brains of rodents and humans [12,13]. The GLP-1 receptor agonists
exendin-4, liraglutide, lixisenatide, and (Val8)GLP-1 have neuroprotective properties. The
protease resistant and long-lasting GLP-1 analogue Val(8)GLP-1 enhanced synaptic plasticity
in acute and chronic application and preserved synaptic functionality in the brains of a mouse
model of AD [14,15]. The novel GLP-1 analogue liraglutide lowered plaque formation,
protected memory and synaptic plasticity, and reduced inflammation in the brains of a mouse
model of Alzheimer disease [16]. All of these effects in the brain were observed after
peripheral injection. Therefore, it is likely that these peptides have to be able to cross the
blood brain barrier (BBB).
The focus of this study was to measure the kinetics of incretin drugs of crossing the blood
brain barrier, activation of incretin receptors by measuring cAMP levels, and physiological
effects in the brain on cell proliferation and neurogenesis.
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