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On
the left are the Red Hot Chili Peppers. I am most interested in the
member
on the right – Flea. Acknowledged as the second best rock
bassist
of all time (right behind John Entwhistle), he gathers as much
or
more attention for his name choice and his seeming inability to
wear
a shirt. On the right is Donnie Thornberry, of the Wild
Thornberrys.
He was a feral child raised by animals in Africa. His
character
is voiced by Flea – ahhh, it’s starting to make sense.
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I use this story to introduce today’s topic - there is so
much more to the capsaicin in chili peppers than just heat and pain. We learned last week how capsaicin and other TRPV1 agonists can combat obesity and damage
from stroke, but these abilities were related to the TRPV1 function in
thermoregulation. Today let’s look at some functions that are so far outside
normal TRPV1/capsaicin function that they can be considered exceptional – like
jazz piano from the RHCP.
Hearing
We have explained the mechanism of hair cell action in hearing before. The inner hair cells are
bent by the sound wave in the cochlea and converted to a neural impulse to be
detected as sound. The outer hair cells
work to amplify the wave so that the sound is louder and can register a signal
in the inner hair cells.
Scientists know that TRPV1 is expressed on the inner and outer hair
cells, and works in the cochlear amplification system particularly. However, we
don’t know its exact function(s) there. On the down side, we know that TRPV1 must
work in a narrow range, because drugs and agonists that excite TRPV1 can lead
to hearing problems.
Acoustic injury (acute or chronic loud noise), gentimicin (an
antibiotic), and cisplatin (a cancer drug) can all cause hearing damage. A 2009 study of gentimicin damage to the cochlea showed that it increased TRPV1
expression in the outer hair cells. A 2008 study of cisplatin showed that its
damage to the hair cells could be suppressed if you decreased TRPV1 activity.
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Most
often people think of tinnitus as a ringing in the
ears,
but it doesn’t have to be. It can be clicking, buzzing,
hissing,
or roaring sounds as well. If you hear voices –
well,
that’s something completely different. Also, tinnitus
is
usually characterized as a neural transduction issue,
often
from damage to the hair cells, so only you hear it.
But
there are problems in blood vessels, muscles, or
bones
(TMJ) near the ear that produce soucnds other
can
hear. This is called objective tinnitus.
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So we see that a little TRPV1 activity is good, but too much
is bad. This is not to say that eating a lot of peppers will harm your hearing;
dietary capsaicin never gets to your cochlea unless you’re a horribly messy
eater. We will return to this idea with TRPV1 and capsaicin; it can be an angel or
a devil.
Memory and learning
Neural plasticity (the ability to change neural connections,
building some, losing others) is important in learning and memory. We have discussed long-term potentiation (LTP) in terms of memory, where a reinforcement of action potentials between
two neurons or in a pathway lead to a strong connection and a new item learned
or remembered.
The flip side is long-term
depression (LTD). This mechanism is what allows you to weaken and lose
connections between neurons that aren’t being reinforced. You can’t learn
something as well unless you keep reinventing the connections, including losing
some. However, don’t get the idea that you have to forget some thing in order
to remember something new, it is much more complicated than that.
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This
is a good carton because it helps me point out a
dichotomy.
Many people say that your brain is a muscle,
if
you don’t exercise it, you will lose it. This is like the
atrophy
of your muscles if you don’t use them. But we are
reading
in this post that losing some neural connections
is
important for learning. Long term depression is similar
to
not using your brain. Those connections that are not
reinforced
are lost – but here it is a good thing,
a
necessary thing.
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TRPV1 acts at the level of the hippocampus (important for
memory) through an endocannabinoid called anandamide. We already know that anandamide is a TRPV1 agonist. A 2008 study indicated that there was no LTD
activity in mice that had no TRPV1 channels. This study found that TRPV1 was
“necessary and sufficient” for LTD, meaning that it was needed and only it was needed for the effect.
Another 2008 study points out how this is important for us. Stress
brings too much LTD and not enough LTP. When you’re stressed it’s harder to
learn new things and easier to lose established knowledge. Amazingly, TRPV1
agonists like capsaicin can regulate this in stress. Stress + TRPV1 agonists
led to reduced LTD and improved LTP. It seems that capsaicin and other TRPV1
agonists regulate synaptic plasticity in both directions, keeping us on balance
and always learning.
Reproduction
Put simply, without capsaicin channels none of us are here to read this
great stuff. TRPV1 activity, through various agonists, is important for sperm
motility and fertilization of the egg. The sperm meets the egg and here we go
- is that the whole picture? Nope. It takes a lot to arrange their introduction,
and some of it involves TRPV1 channels.
You ever wonder why the testicles are kept outside the trunk
of the body? It’s to keep the sperm cool – heat kills sperm. TRPV1 receptors
sense high heat and institutes local reactions to cool the sperm. A 2008 study
showed that TRPV1 knockout mice had much higher levels of sperm death in the
testicle when the temperature was raised. It didn’t make the mice sterile, but it was close.
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On
left is a cartoon of sperm capacitation, making it ready tofertilize
travel to the egg. The loss of the cholesterol coat isimportant
for increasing motility and for finishing the signals that point
out whee the egg is. The acrosome is also prepared here, but there
are more acrosome changes in the right image showing the
acrosome
reaction. Here, the spem head becomes a weapon, dissolving
the outer layers of the egg and stabbing it for entry.
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TRPV1 and endocannabinoid receptors are also responsible for
the increase in sperm motility after capacitation. The sperm swim toward the
egg, but how do they know where she is? There are many signals, including
osmolarity differences, hormones, temperature changes, pH changes, and liquid
currents. We have seen that several of these (pH, temp., hormones, osmosis) are
sensed by TRPV1 channels.
It’s been shown that TRPV1 on the sperm post-acrosomal and
head regions are important for sperm motility. A 2013 study showed that
inhibiting TRPV1 slowed down fish sperm. And in a 2013 study of infertile men,
the motility of the sperm in men with low levels of anandamide was decreased.
Strangely, even though capacitated sperm are thermotactic
(swim toward higher temperatures), this is one time where it DOESN’T involve
TRPV1/capsaicin receptors. It still involves calcium, but the flux is through a
different receptor system.
Once the sperm finds the egg, it undergoes the acrosome reaction. This makes it
possible for the sperm - only one mind you - to enter the egg. A 2009 study indicated that anandamide and
TRPV1 are crucial for the acrosome reaction as well.
From inside the male, to inside the female, to inside the
egg, capsaicin receptors are crucial for making tiny humans. It doesn’t get
more important than that. What I don’t know is if eating peppers affects any of
this. Would a habanero make you more fertile or less?
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The
PSA test (prostate specific antigen) can be used
for
monitoring treatment of prostate disease as well
as
for diagnosis of prostate cancer in conjunction with
other
tests. The tests measure s aprotein produced by
the
prostate that is often elevated in those with prostate
cancer.
PSA can be free or bound to a protein. You want
the
free:bound ratio to be high, and low ratio is more
indicitive
of cancer. However, there are noncancerous
reasons
for an elevated PSA, so don’t go nuts if your
levels
ar higher than normal (score of 4 ng/ml).
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In cancer we see the dual nature of TRPV1 again.
In some cases it prevents or stops cancer, while in others, capsaicin might
contribute to cancer.
Prostate cancer has been studied a lot with respect to
TRPV1. Capsaicin, in particular, has an effect on prostatic cancer cells. It
kills the cells and reduces tumor size in mice. However, in humans, little work
as been done. One epidemiology study found that Nigerians that eat more peppers
have a lower rate and later onset of prostate cancer.
In addition, a single study followed a man whose prostate cancer returned after several disease free years. His PSA value
(prostate specific antigen, a sign of cancerous growth) started to double
weekly, so he started taking 2 ml habanero sauce once or twice week. His PSA
value increases slowed by half. He stopped and they sped up. He started daily
habanero sauce and the PSA dropped.
Sounds like a treatment to me.
The mechanisms of capsaicin action on prostate cancer cells
has been determined in in vitro work.
They are both TRPV1 dependent and TRPV1 independent. (studies) Capsaicin
increases ROS, induces apoptosis, destabilizes membranes, throws off ion
balances…basically everything capsaicin stops
when used for protective hypothermia (from last week).
It isn’t just prostate cancer where capsaicin may help. In a
mouse model of lung cancer, giving capsaicin prevent the lung tumors from
forming by increasing apoptosis in the cancerous cells. Whether this is
TRPV1 dependent or independent was not discussed.
But there is a darker side to capsaicin and TRPV1 in
prostate cancer. The agonists have a small window of effectiveness. Low levels
actually promote cancer growth, but higher levels cause cell cycle arrest and
apoptosis. In one study, 10 µM capsaicin actually created prostate tumors in
mice.
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Where
do you come down on the question of whether
peppers
are good for you or not? Do they cause cancer
or
prevent it? Do they cause pain or prevent it? I think
that
as with most things, moderation is the key. Too
much
of anything is bad for you, except maybe this blog.
One
thing I do know; we have sharp canines for a reason -
we
were meant to eat meat. This statement is why
she
has that look on her face.
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In squamous cell skin cancer, capsaicin can sometimes stunt the growth of tumors via apoptosis, but the mechanism seems to be TRPV1
independent, since a TRPV1 antagonist brings the same effect. The take home
message is that TRPV1/capsaicin effects may be diet, individual, cancer
specific. This will make it hard to develop therapeutics.
Next week - now its time to start talking about cool receptors. Like how the cigarette companies use "cool" to sell smokes.
For
more information or classroom activities, see:
Cochlear
amplification –
Tinnitus
–
Sperm
capacitation –
Acrosome
reaction –
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