Alisha Kodibagkar

Research Assessment #5
Date: Sept. 21, 2016
Subject: Traumatic Brain Injury- potential therapeutic drug
MLA Citation(s):
Pharmaceutical Formulation & Quality Magazine, Steve Campbell. "TBI's Miracle Drug." T
BI's
Miracle

Drug. WETA, 2015. Web. 27 Oct. 2016.

Assessment:
Earlier this week, I further refined my interest within the fields of neuroscience and
biomedical engineering and determined that I am interested in brain injury in particular. While my
previous articles have been about various aspects of neuroscience, I have decided to narrow
down my research to this topic because it is one I am greatly interested in.
My article for this assessment is about the discovery and applications of a drug which
may play an important role in healing the brain after traumatic brain injury (TBI). The article
began with an overview of traumatic brain injury and its impact on people through loss of life,
disability, and costs.After discussing TBIs effects, the drug cyclosporine is introduced as having
neuroprotective capabilities. From here, the article explains the two stages of brain injury: the
initial and secondary stages. While the initial stage is the physical injury occurring, the secondary
stage is a series of cascading interactions that cause the death of brain cells. This stage
increases the injury and disability which occurs after TBI. After this, the author discusses the role
of mitochondria in TBI. When injury occurs, calcium increases in the brain, and the uptake of
calcium uses up the mitochondria's energy production. Because of this pores form in the
membrane of the mitochondria (also called mPT) leading to an eventual collapse of mitochondrial
structure which leads to cell death. Cyclosporine targets the mPT and can enter the brain during
blood-brain-barrier compromise after injury, protecting mitochondria. The article talks about the

Alisha Kodibagkar

discovery of cyclosporine and then its application. The last section of the article explains that the
product NeuroSTAT, which is a version of cyclosporine, will continue to be tested with the
European Brain injury Consortium, so hopefully it will eventually be used against the effects of
Traumatic Brain Injury. A problem also discussed in the article is the challenge of transitioning
from promising animal studies to real clinical human benefits.
This information is relevant to my topic because it is focused on the area within my topic
that I have decided to focus my research on: brain injury. TBI is a crucial area of study because,
as of now, there arent any treatments used to prevent the secondary injury. I liked reading about
how therapeutic drugs can function and help heal brain injury, because this is an aspect of TBI I
did not look into before. My past studies have been on how the injury occurs and how to target
proteins in the brain to bring in drugs, but I never did research specifically on the drugs
themselves. What Ive learned enhances my previous knowledge on this specific subtopic.
By reading this article, I have gained a new perspective on TBI as well as its future. I was
surprised at the efficiency of cyclosporine in improving brain injury in animals and, in addition,
was somewhat surprised to find that the results werent as great in human clinical trials. My
prediction is that this is because brain injury is controlled in animal experiments, so particular
types of brain injury are repeated in similar ways, whereas real-life human brain injury is not
usually as homogenous. I am curious to know if this is the case and/or if there are some
fundamental differences between the animals and the humans which causes the lack of
correlation.
Through this article I have gained an interest in the process of translation from animal
trials and clinical trials. In addition, I learned a lot about the drug cyclosporine and the cellular
component of its function which I found to be very interesting. From now onwards, I hope to keep
my research more specific and to learn more about the process of brain injury on the cellular

Alisha Kodibagkar

level. I also am excited to learn about new perspectives on the future and implications in this
field.

TBI's Miracle Drug

An accidental discovery about 20 years ago has led
to a cyclosporine pharmaceutical on the threshold of
approval.
Often called the silent epidemic, traumatic brain injuries (TBIs) afflict approximately 1.7 million
Americans annually. More than 52,000 are killed, and 275,000 are hospitalized.1 Most are left in
various states of disabilityfrom almost-full recovery, to mild symptoms but able to function with
some or moderate disability, to severe disability requiring around-the-clock intensive care and
support. The annual direct and indirect cost of TBIs, such as lost work time or reduced
productivity, have been estimated at more than $60 billion, and there may be more than six
million TBI survivors in society with some disability.2
Over the past decade, TBI has come to the fore as tens of thousands of wounded soldiers return
home from the Middle East suffering hidden or visible TBIs and trauma caused by blast injuries
from improvised roadside explosions.3 What is called post-traumatic stress disorder may actually
be the long-term after-effects of TBI.

Due to the economic and social costs of TBI, a significant ongoing effort is being made to develop
and apply emerging new clinical and preclinical pharmaceuticals that hold the potential in
post-injury medical treatment to mitigate the cascading additional brain damage that occurs
during the critical secondary phase in TBIs. Among these is an interesting pharmaceutical
compound called cyclosporine (also known as cyclosporin-A, or CsA) that has been found to have
significant neuroprotective capabilities and the ability to moderate the resulting damage and
long-term disability in TBI.4,5,6,7
Preclinical mouse model studies show an 80% reduction in neural damage through the application
of this pharmaceutical.8, 9 More than 17 years in development for neuroprotection, CsA is working
its way toward approval as a treatment to greatly ameliorate the effects of TBI in humans.

Two Stages

Alisha Kodibagkar

There are two stages in traumatic brain injuries. The first stage occurs at the time of injury, for
example due to a gunshot, blast, fall, or hit. This initial stage could be either a closed-head or
open-wound injury, and medical emergency personnel focus on treating the wound or injury and,
importantly, stabilizing the patients vital signs.
The secondary stage of damage to the brain takes place after the initial insult, as the injury
continues to ripen and worsen in the hours and days after the initial trauma. This is when the
doctor says, Now we just wait and see, as theres nothing more that medicine can do. In this
secondary stage, the trauma to the brain triggers a series of cascading intracellular biochemical
reactions that end up causing severe demise of brain cells, brain damage and expanded disability.
If this secondary stage can be mitigated, the eventual damage and disability can be greatly
reduced, enabling the victim to get closer to full recovery.
Some of the secondary-stage mechanisms believed by researchers to be involved in brain-cell
death after TBI include uncontrolled release of signalling molecules (neurotransmitters), cellular
calcium overload, inflammation, energy failure, oxidative damage, and the overactivation of
enzymes such as calpains and caspases.10
All of these are believed to create the intracellular and extracellular conditions that lead to the
destruction of millions of additional brain cells, and the damage and disability that result. Many of
these are being targeted by a variety of pharmaceutical compounds and medical treatments (such
as forcing oxygen into the brain through the use of hyperbaric chambers) that are in various
stages of clinical development.11 By targeting the protection of mitochondria inside brain cells,
cyclosporine is perhaps the most promising of these.

Role of Mitochondria
Research confirms that mitochondria, as the cellular energy (ATP) producers inside the brain cells,
play a pivotal role in neuronal cell death or survival, and that mitochondrial dysfunction is
considered an early event in brain injuries that causes neuronal cell death. The uncontrolled
release of signalling molecules with resulting overstimulation/stress of brain cells and
accumulation of high levels of intracellular calcium may be the initial mechanism that leads to
neuronal cell death.12
How does this affect brain cells? Increases in calcium lead to its rapid uptake into the
mitochondria (which act as cellular sinks for calcium). However, the excessive transport and
uptake of calcium will negatively impact mitochondrial energy production, as the driving force for
ATP production and calcium transport both rely on the proton motive force (the proton gradient
created over the mitochondrial inner membrane by the respiratory chain). Further, excessive
calcium uptake by mitochondria, in combination with energy failure, leads to the formation of
protein channels (pores) in the inner membranethe induction of the so-called mitochondrial
permeability transition (mPT).
The increased permeability of the inner membrane caused by the mPT pores immediately
collapses mitochondrial function and structure (when the pores are opened, the osmotically active
inner compartment (matrix) of the mitochondria will attract water and the mitochondria will swell
and pop like balloons). In addition to causing the cessation of energy production, upon induction

Alisha Kodibagkar

of the mPT the stored calcium and harmful proteins will then be released from mitochondria,
resulting in an avalanche of further mitochondrial collapse, cellular energy depletion, and
subsequent cell death. When brain-cell death is repeated millions of times during the cascading
biochemical imbalances that characterize the secondary phase, the extent of brain damage and
eventual disability is greatly increased.13
Protecting the mitochondria by targeting the mPT is a viable neuroprotective approach that has
emerged in the last decade. Published research has found that the protein cyclophilin D is an
essential component in opening the mPT pores,14 and that cyclosporine binds to cyclophilin D and
inhibits the induction of mPT.15 The result is that mitochondria can absorb much more calcium
without collapsing, allowing them to survive. As mitochondria survive to produce energy for the
brain cell, fewer brain cells die during the secondary stage. This is the core battleground in the
war against TBIs.

Cyclosporine Protects
Cyclosporine was discovered in 1969 when it was first isolated from the fungus Tolypcladium
inflatum in Norway by researchers working for Sandoz (now Novartis). Its impressive

immunosuppressive properties led it to become a pharmaceutical to prevent tissue rejection in

organ transplant patients. It has been in use for immunosuppressive applications since the early
1980s as a commercially successful Novartis product called Sandimmune.16
CsAs ability to protect the mitochondria in the brain by binding to cyclophilin D and preventing
the induction of the mPT was later discovered in 19931994, a period during which medical
researcher Eskil Elmrand his Japanese colleague Hiroyuki Uchino working in Sweden were
conducting experiments in cell transplantation. An unintended finding was that CsA was strongly
neuroprotective when it crossed the bloodbrain barrier.17 The startling discovery became the
starting point for basic research and patent applications in this promising new avenue of
neuroprotection that have continued and expanded to the present day.
The fundamental research mapping out CsAs extensive neuroprotective capabilities has been
running continuously since 1993, and many international and independent research teams have
since conducted and published numerous studies confirming that CsA is a powerful nerve-cell
protector in TBI, stroke and brain damage associated with cardiac arrest. Advanced studies also
show that CsA is useful in protecting mitochondria in heart tissue facing reperfusion injury during
heart attacks (see sidebar).18
Together with U.S. neurosurgeon Dr. Marcus Keep, Dr. Elmrand his colleagues formed a
company with the aim of commercializing and patenting their work of developing
cyclosporine-based products for acute conditions and diseases affecting the brain. In 1999, the
U.S. patent was approved and, in 2000, their CsA product name NeuroSTAT was registered. Later,
the patent portfolio around CsAs impact on the CNS, cardiac and other areas was expanded
greatly under their company NeuroVive Pharmaceutical AB (Sweden).
Today, NeuroVives NeuroSTAT version of cyclosporine is a fully developed product. An important
advancement in NeuroSTAT is that its formulation is made using a patented non-allergenic lipid
emulsion to keep CsA as a lipophilic drug in solution.

Alisha Kodibagkar

Next Steps
Its been almost two decades since Eskil Elmrand his colleagues first discovered cyclosporines
neuroprotective capabilities and there is still some way to go. However, CsAs promise as a TBI
pharmaceutical continues to make progress. Full commercialization is now in sight.
In 2010, NeuroSTAT received orphan drug status from both the U.S. FDA and in Europe for the
treatment of moderate and severe TBI. In March 2011, the company announced it would be
working with the European Brain Injury Consortium to conduct a phase II/III adaptive study on
NeuroSTAT.19 These clinical trials should provide the basis for the registration of NeuroSTAT in
Europe, and possibly the U.S. and elsewhere. U.S.-based clinical trials are also being planned, and
NeuroVive is seeking partnering organizations in China for similar trials.
Of course, the challenges in such trials, where many TBI drugs have failed in the past, are to
translate promising animal study research results into clinical benefits in humans, and be able to
recruit sufficient patients within a reasonable time frame. Whats most exciting and unique for
NeuroSTAT is that cyclosporine has already been shown in a small-group human study published
in the New England Journal of Medicine (NEJM) in 2008 to deliver a 40 percent reduction in heart
damage from reperfusion injury in myocardial infarction.20

Since the mechanism of cyclosporines ability to protect mitochondria in acute injury is the same
in TBI as it is in reperfusion injury, NeuroSTATs future prospect as a pharmaceutical to treat
moderate to severe TBI appears exceptionally promising.
At the same time, an NEJM editorial called for follow-up studies to fully determine cyclosporines

capacity to reduce reperfusion injury.21 In April 2011, a 1,000-patient investigator-initiated phase

III study in Europe enrolled its first subject; it is expected to be completed in 2013. The study is
using NeuroVives CicloMulsion (the trade name of NeuroSTAT for the reperfusion injury market)
and will conclude with 12 months of follow-up with all patients.22
Assuming all goes according to plan with its clinical studies, cyclosporines early promise from its
serendipitous discovery as a neuroprotectant in the 1990s could be fulfilled within the next two to
five years. Then neurologists and neurosurgeons worldwide will finally be able to trumpet that
they have an exciting new weapon in their war against the silent epidemic and onslaught of
traumatic brain injuries.