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TBI's Miracle Drug

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Steve Campbell, Pharmaceutical Formulation & Quality magazine

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 disability—from 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

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 patient’s 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 there’s 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 membrane—the 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 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

CsA’s ability to protect the mitochondria in the brain by binding to cyclophilin D and preventing the induction of the mPT was later discovered in 1993–1994, a period during which medical researcher Eskil Elmérand 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 blood–brain 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 CsA’s 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. Elmérand 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 CsA’s impact on the CNS, cardiac and other areas was expanded greatly under their company NeuroVive Pharmaceutical AB (Sweden).

Today, NeuroVive’s 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.

Next Steps

It’s been almost two decades since Eskil Elmérand his colleagues first discovered cyclosporine’s neuroprotective capabilities and there is still some way to go. However, CsA’s 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. What’s 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 cyclosporine’s ability to protect mitochondria in acute injury is the same in TBI as it is in reperfusion injury, NeuroSTAT’s 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 cyclosporine’s 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 NeuroVive’s 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, cyclosporine’s 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.

About the author:

Steve Campbell is a writer and communications consultant in Vancouver, B.C., who writes for and about pharmaceutical and scientific research, products and companies. He can be reached at scampbell@campbellpr.bc.ca.


1. Statistics on Traumatic Brain Injury. Source: Centers for Disease Control. www.cdc.gov/traumaticbraininjury/statistics.html

2. Ibid.

3. Hoge C, McGurk D, Thomas J, et al. Mild traumatic brain injury in U.S. soldiers returning from Iraq. The New England Journal of Medicine. 2008; 358 (5): 453-463.

4. Sullivan P, Sebastian A, Hall E. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. Journal of Neurotrauma 2011 Feb;28:311-318.

5. Hansson, MJ, Morota S, Chen L et al. Cyclophilin D-sensitive mitochondrial permeability transition in adult human brain and liver mitochondria. Journal of Neurotrauma 2011 Jan;28(1):143-53.

6. Mazzeo AT, Brophy GM, Gilman CB, Alves OL, Robles JR, Hayes RL, Povlishock JT, Bullock MR. Safety and tolerability of cyclosporin a in severe traumatic brain injury patients: results from a prospective randomized trial. Journal of Neurotrauma. 2009; Dec;26(12):2195-2206.

7. Cook AM, Whitlow J, Hatton J, Young B. Cyclosporine A for neuroprotection: establishing dosing guidelines for safe and effective use. Expert Opinion on Drug Safety. 2009 Jul;8(4):411-419.

8. Sullivan P, Sebastian A, Hall E. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. Journal of Neurotrauma 2011 Feb; 28 (2) 311-318.

9. Sullivan P, Thompson M, Scheff W. Continuous infusion of cyclosporin A post injury significantly ameliorates cortical damage following traumatic brain injury. Experimental Neurology 2000 Feb; (161: 631-637.

10. Loane J, Faden A. Neuroprotection for traumatic brain injury: translational challenges and emerging therapeutic strategies. Trends in Pharmacological Sciences 2010 Dec. 31;(12):596-604.

11. Ibid.

12. Mazzeo AT, Beat A, Singh A, Bullock MR. The role of mitochondrial transition pore, and its modulation, in traumatic brain injury and delayed neurodegeneration after TBI. Exp Neurol. Review. 2009 Aug; 218(2):363-730. Epub 2009 May 27.

13. Ibid.

14. Schinzel A et al, Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proceedings of the National Academy of Sciences. 2005 102: (34) 12005-12010.

15. Waldmeier PC, Zimmerman K, Qian T, Tintelnot-Blomley M, Lemasters, J, Cyclophilin D as a drug target. Current Medicinal Chemistry 2003 10: (16) 1485-1506.

16. http://www.pharma.us.novartis.com/product/pi/pdf/sandimmune.pdf

17. Uchino H, ElmérE, Uchino K, Lindvall O, Siesjo BK. Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat.Acta Physiologica Scandinavica. 1995 Dec;155(4):469-471.

18. Piot C, Croiselle P, Staat P, et al. Effects of cyclosporine on reperfusion injury in acute myocardial infarction. The New England Journal of Medicine. 2008; 359 (5): 473-481.

19. www.neurovive.com

20. Piot C, Croiselle P, Staat P, et al. Effects of cyclosporine on reperfusion injury in acute myocardial infarction. The New England Journal of Medicine. 2008; 359 (5): 473-481.

21.Hausenloy D, Yellon D. Time to take myocardial perfusion injury seriously. The New England Journal of Medicine. Comment. 2008; 359 (5): 518-520.

22. www.neurovive.com

Editor’s Choice for further reading

  1. Vaishnavi S, Rao V, Fann JR. Neuropsychiatric problems after traumatic brain injury: unravelling the silent epidemic. Psychosomatics. 2009; May-Jun;50(3):198-205.
  2. Dekosky S, Ikonomovic M, Gandy S. Football, warfare, and long-term effects. Perspective. The New England Journal of Medicine. 2010; 363 (14): 1293-1296.
  3. Piot C, Croiselle P, Staat P, et al. Effects of cyclosporine on reperfusion injury in acute myocardial infarction. The New England Journal of Medicine. 2008; 359 (5): 473-481.
  4. Sullivan P, Sebastian A, Hall E. Therapeutic window analysis of the neuroprotective effects of cyclosporine A after traumatic brain injury. Journal of Neurotrauma 2011 Feb; 28 (2) 311-318.
  5. Schinzel A et al, Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proceedings of the National Academy of Sciences. 2005 102: (34) 12005-12010.

Used with permission by Steve Campbell and Pharmaceutical Formulation & Quality magazine. The article was first published in Pharmaceutical Formulation & Quality magazine, August/September 2010. www.pharmaquality.com. Article link  http://www.nxtbook.com/nxtbooks/wiley/pfq_20110809/#/16.

Comments [5]

To the person who said that they had brain damage from Sertraline. I understand that completely. That's the reason why I was Googling brain damage from medication when I found this site. There is a lot of us that have had brain damage from these medications. I would love to talk to you. There was a Facebook group with over 2000 members that I was administrator in. I started to recognize the people that this has happened to. Myself being one of them. I don't know if you'll get this message but if you do please contact me. I was thinking about putting together a Facebook group for people that have had damage from these medications and what we can do to get better. Something has definitely happened to my brain and I have the symptoms of TBI just from taking medication. My email is Hmariewv@hotmail.com

Dec 17th, 2016 3:58pm

will this help me? I had brain injury due to medicines Sertraline 50 milligram and alprazolam .5 milligramcan. Somebody please help. I feel that I am terminal due to this.

Sep 26th, 2016 6:11pm

Will it help me? after 5 years? tbi sucks!

Oct 14th, 2012 7:09pm

Reactions in your body produce chemicals called oxidants that damage cells and shorten life. To protect your cells from oxidant damage, your body produces antioxidants such as superoxide dismutase and coenzyme Q10. Since tissue levels of coenzyme Q10 drop with aging, it is tempting to think that reduced levels of this coenzyme cause aging. However, research shows that lowered levels are the result of aging rather than the cause because coenzyme Q10 is found in the mitochondria, the energy sources of cells. With aging, the number of mitochondria and size of cells become smaller, so everything in the mitochondria is reduced. Furthermore, coenzyme Q10 has been found to be ineffective in treating diseases affecting the mitochondria (2). Since coenzyme Q10 is a source of energy, doctors thought that coenzyme Q10 supplements would increase endurance, but studies show that it does not (3). Years ago, a researcher at the University of Texas showed that people who have arteriosclerotic heart disease have lower blood levels of coenzyme Q10 than people who have normal hearts. People with damaged hearts have less functioning heart muscle, so they should have lower levels of coenzyme Q10. For coenzyme Q10 to improve health and energy, it must get into the cells, particularly the mitochondria, where it functions. Studies show that coenzyme Q10 pills get into the bloodstream, but cannot be recovered in the cells (6). Therefore coenzyme Q10 pills cannot get into heart muscle and kidneys (4), so they cannot strengthen a failing heart. 1) Nutrition News POB 55279 Riverside, Cal 92517. 1987 volume X, number 8. 2) Mathews PM et al. Coenzyme Q10 with multiple vitamins is generally ineffective in treatment of mitochondrial disease. Neurology. 1993(May);43(5):884-890. 3) Porter DA et al. The effect of oral coenzyme Q10 on the exercise tolerance of middle-aged, untrained men. International Journal of Sports Medicine 1995(Oct);16(7):421-427. 4) Zhang Y et al. Uptake of dietary coenzyme Q supplement is limited in rats. J. Nutr. 1995(Mar);125(3):446-453. 5) Y Birnbaum, SL Hale, RA Kloner. The effect of coenzyme Q(10) on infarct size in a rabbit model of ischemia/reperfusion. Cardiovascular Research 32: 5 (NOV 1996):861-868. Conclusions: Coenzyme Q(10), administered acutely either during or 60 min before myocardial ischemia, does not attenuate infarct size in the rabbit. 6) M Svensson, C Malm, M Tonkonogi, B Ekblom, B Sjodin, K Sahlin.Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism during high-intensity exercise. International Journal of Sport Nutrition, 1999, Vol 9, Iss 2, pp 166-180. Q10 supplementation increases the concentration of Q10 in plasma but not in skeletal muscle. From Drmirkin.com http://www.drmirkin.com/nutrition/7883.htm Summarizing: Coq10 has not been shown to have any effect. Your best bet is to exercise and strengthen the mitochondria (in all cells, brain as well as muscle) that way.

Sep 6th, 2012 3:47pm

So why wouldn't you give TBI patients Co Q 10 to preserve mitochondrial function?

May 7th, 2012 8:33pm

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