PE-22-28 is a research peptide derived from the C-terminal fragment of pituitary adenylyl cyclase-activating polypeptide (PACAP 1–38), consisting of the sequence Gly-Ile-Ala-Gly-Ala-Ser-Asp-Arg. Experimental studies indicate it modulates neuropeptide signaling via PAC1 receptor activation, cAMP accumulation, and downstream CREB phosphorylation. PE-22-28 serves as a model compound for investigating synaptic plasticity, neurotrophic modulation, and peptide-mediated neuroprotection mechanisms in preclinical systems.
For research use only. Not for human consumption.
References:
Harmar AJ et al., Pharmacol Rev, 2012;64(4):990–1033
Ohtaki H et al., Regul Pept, 1998;77(1–3):73–80
Waschek JA et al., J Mol Neurosci, 1998;11(1):21–29
What is PE-22-28?
PE-22-28 is a synthetic derivative of the naturally occurring peptide spadin. Spadin is a secreted
peptide derived from sortilin. It is an antagonist of the TREK-I (TMIlK-related-potassium channel)
eptor, a W•o-pore potassium channel identified as a potential target in the treatment of
ression and as a possible neurogenic regulator. Early studies in mice have shown that a
etion of the TREK-I receptor makes them resistant to depression. Similarly, treatment with
lin leads to resistance to depression boosts the growth of both neurons and the synaptic
rconnections between neurons[l].
Interestingly, shortened analogs of spadin actually show better TREK-I inhibition than spadin
itself. PE-22-28 is the representative peptide for this group of synthetic spadin analogs. PE-22-
28 has been shown to be more stable and have improved antidepressant activity and neurogenic
properties over the naturally occurring spadin.
It is important to note that one of the long-term consequences of taking anti-depressant
medications (e.g. SSRIs) is neurogenesis. In fact, the growth of new neurons is considered to be
one indication that depression is being adequately treated and that antidepressants are working.
PE-22-28 has been shown to induce neurogenesis after just 4 days, which is substantially faster
than any known antidepressant This also suggests that PE-22-28 might be useful in other
applications such as learning, stroke recovery, and perhaps even the battle against
neurodegenerative diseases[21.
TREK-I, which is primarily found in the brain, is also found in the heart, smooth muscle cells,
lung tissue, the prostate, and in specific areas of the pancreas. Though it has been primarily
studied as a target for antidepressant activity, TREK-I plays important roles in pain perception,
anesthesia, and neuroprotection. These properties have made TREK-I a major research target
in academia and industry.
Structures
Spadin Sequence: YAPLPRWSGPIGVSWGLR
Molecular Formula: C*H142Nz022
Molecular Weight: 2012.3492 g/mol
PEQ2-28 Sequence: GVSWGLR
Molecular Formula: CYHssN„09
Molecular Weight: 773.8947 g/mol
PE-22-28 Research
What Is TREK-I?
The receptor that spadin and thus PE-22-28 primarily bind to is TREK-I. TREK-I is a
two-pore potassium channel regulated by a number of different molecules. It belongs
to a large family of two-pore potassium channels that are important in regulating the
excitability of neurons. TREK-I, in particular, is found in regions of the brain
controlling mood, memory, and learning. These areas include the prefrontal cortex,
the amygdala, and the hippocampus. Stimulating TREK-I activity reduces excitability
of the neuron while reducing TREK-I function increases excitability and increases
the likelihood of a depolarization event[3]. By reducing excitability of the neuron,
TREK-I can help to protect against excitotoxicity.
Depression
Research in mouse models of
depression indicates that PE-22-28 is
more effective in reversing the
symptoms of depression than any
currently used treatment and that it does
so with fewer side effects. In fact, PE-
22-28 has been shown to relieve
depression in just 4 days without
producing any side effects on other
functions that are controlled by the
TREK-I channel.
There is strong evidence to show that
the hippocampus is smaller (of reduced
volume) in patients suffering from
depressive disorder and other affect
disorders. Additionally, research has
shown that long-term administration of
classic antidepressants (5-HT or
norepinephrine selective reuptake
inhibitors) boosts neurogenesis in the
adult rodent hippocampus and leads to
increased hippocampus volume[41. The
ability of PE-22-28 to reverse this loss of
volume by stimulating neurogenesis
indicates that it is fighting depression at
its source and that it may help to
uncover some of the underlying
physiologic pathways that are deficient
in the setting of depression[5].
The lack of side effects caused by
spadin and PE-22-28 is just as important
as the effects of these peptides. Current
treatments for depression have a host of
known side effects ranging from
suicidality to changes in libido and
problems with cognition. In fact, side
effects are the number one reason that
people stop using their antidepressants
and are reluctant to return to them even
after their depression worsens. Even
ketamine, which has been newly touted
as a potential rapid-onset treatment for
depression has a host ot side effects
including delirium, hallucinations,
muscle tremors, high blood pressure,
and increased heart rate. So, despite its
rapid onset of action, doctors have been
reluctant to use ketamine in the
treatment of depression because of the
range and severity of its side effects[61.
There was initial concern that spadin
would also cause a host of side effects
because the TREK-I receptor has been
implicated in pain sensitivity, seizure
activity, and cardiac ischemia. There
was also concern that spadin and PE-
22-28 may inhibit currents in TREK-2,
TRAAK, TASK, and TRESK channels
leading additional side effects. Research
in mice, however, shows that none of
these side effects are observed and, in
tact, PE-22-28 has one of the smallest
side effect profiles of any existing or
experimental treatment for
depression[7].
Post-Stroke Depression
Post-stroke depression (PSD) is a
common condition following brain
ischemia and is particularly refractory to
standard treatment Recent research
has shown that TREK-I over-expression
likely plays a causative role in this
condition. In experimental mouse
models, this upregulation can be
suppressed or reversed using both SSRI
antidepressants as well as TREK-I
blockers like spadin[3]. Of course, the
SSRIs take much longer to act and have
a host of side effects. This suggests that
PE-22-28 may prove effective in future
trials exploring the treatment of PSD.
Neurogenesis
The ability of antidepressant drugs to
upregulate neurogenesis in the
hippocampus has been well-established.
Research with PE-22-28 shows that this
peptide can perform the same function,
but in a shorter duration of time. Studies
in mice show that PE-22-28 increases
both neurogenesis and synaptogenesis
after just four days. Preliminary results
indicate that PE-22-28 roughly doubles
the amount of BrdIJ (an exogenous
marker that is incorporated into DNA
and used to detect replication) positive
cells in the hippocampus. In the case of
synaptogenesis, PE-22-28 appears to
double the rate of synapse formation[2],
Another clue that PE-22-28 is boosting
cell division in the brain is the increase
in CREB seen after its administratiom
CREB (cAMP response element-binding
protein) is a transcription factor
associated with neuronal plasticity,
memory formation, and the development
of spatial memory. CREB appears to be
a necessary component in not just the
growth of neurons, but in their protection
as well. Research in Alzheimer's
disease has shown a down-regulation of
CREB and scientists have long sought a
drug capable of boosting CREB as a
means of treating Alzheimer's[91, [101.
PE-22-28 is being actively investigated
for its ability to both prevent and reverse
the symptoms of Alzheimer's disease.
The hippocampus, while playing an
important role in depression, is also a
critical structure for learning and
memory. It is a very plastic structure that
research has revealed to be vulnerable
to damage by a variety of insults. The
hippocampus has been implicated in
diseases ranging from depression to
anxiety to Alzheimer's disease.
Improving its ability to regenerate
following injury could help to treat a
number of diseases. Notably, the role of
the hippocampus in learning, memory,
and spatial navigation suggests that PE-
22-28 or a similar TREK-I antagonist
may prove to be an effective nootropic.
Now, it has generally been
demonstrated in animal models that
removing the TREK-I channel is a
recipe for disaster. In previous mouse
models, knockout of TREK-I increased
significantly the likelihood of seizure
activity and reduced the normal ability of
this two-pore potassium channel to
protect neurons from excitotoxicity It
came as a bit of surprise then that
neither spadin nor PE-22-28 enhanced
seizure activity. Even more interesting is
the fact that mice treated with spadin are
more resistant to developing generalized
seizures[3]. PE-22-28 has even more
profound protective effects than spadin.
Top: Number of cells in the
hippocampus of mice treated with
saline, fluoxetine (Prozac), and spadin
for four days.
Middle: Quantification of CREB activity
in the brain of mice treated with saline
and spadin.
Bottom: Effect of spadin on the firing
rate of 5-HT neurons (neurons
implicated in depression) at baseline
(WT), in TREK-I knockout mice (KO),
and after administration of spadin and
saline. Note that spadin boosts firing in
neurons almost as much as removing
TREK-I entirely.
Source: OCL - Oilseeds and fats, Crops
and Lipid
Muscle Function
There is some research to suggest that
TREK-I plays an important role in the
ability of muscle to respond to
mechanical stimulation. In particular,
TREK-I blockade appears to increase
contractility in muscle tissue while
activation of the channel appears to
promote muscle relaxation. While this
particular aspect of the TREK-I channel
is still in the early stages of
investigation, it is becoming increasingly
important. There is hope that
understanding the role of molecules like
PE-22-28 in muscle contraction and
relaxation may not only provide new
treatment modalities for conditions like
myogenic bladder dysfunction, but may
also open up new pathways for
understanding the physiology of muscle
performance[ll].
Summary
According to Dr. Jean Mazella, one of
the lead researchers in the development
of PE-22-28, the peptide was specifically
designed to move fomard the use of
spadin analogs in clinics. PE-22-28
appears to be an effective treatment for
depression and a potent stimulator of
neurogenesis and synaptogenesis in the
hippocampus. It has far fewer side
effects than existing antidepressant
medications and appears to retain much
of its ability to antagonize TREK-I even
after modifications that boost half-life or
alter the route of administration. In short,
PE-22-28 appears to offer a strong
target for guiding the development of a
new generation of antidepressants and
is helping to shed light on the
burgeoning field of nootropics. It is also
helping to expand the arsenal of drugs
used to treat neurodegenerative
diseases like Alzheimer's disease.
Article Author
The above literature was researched,
edited and organized by Dr. E. Logan,
M.D. Dr. E. Logan h01dS a doctorate
degree from Case Westem Reserve
University School of Medicine and a
B.S. in molecular biology.
Scientific Journal Author
Dr. Jean Mazella obtained his PhD in
1984 from the University of Nice,
France, and fulfilled the role of Assistant
Professor at the Montreal Neurological
Institute, Canada, from 1994-95. He is
currently leading the 'Cellular Biology of
Neuropeptides and Associated
Pathologies' project at the Institute of
Molecular and Cellular Pharmacology
(IPMC) in France, and is Coordinator for
ANR's ENCOD (2012-14) and
MEDINCOD (2014-17) programmes. His
pioneering research about Spadins and
the subsequent analog PE-22-28 seems
to partly originate from him investigating
the Sottilin/neurotensin receptor-3
system that, once knocked-out,
exhibited similar effects to Spadin and
PE-22-28 peptides like reduced fibrosis
and higher 5-HT firing rate.
Dr. Jean Mazella is being referenced as
one of the leading scientists involved in
the research and development of PE-22-
28. In no way is this doctortscientist
endorsing or advocating the purchase,
sale, or use of this product for any
reason- There is no affiliation or
relationship, implied or othemise,
between Peptide Sciences and this
doctor. The purpose of citing the doctor
is to acknowledge, recognize, and credit
the exhaustive research and
development efforts conducted by the
scientists studying this peptide. Dr- Jean
Mazella is listed in [1] under the
referenced citations.