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Mohammad Ali, nano-medicine and methods of drug delivery



MohammadnAli is one of the best boxers to ever stand in a boxing ring. A three-time world heavyweight champion, Mohammad Ali was convinced that he will not suffer brain injury even after being affected by the thousands of powerful and crippling blows received from his opponents. Jonathan Eig, who spent four years conducting nearly 500 interviews for his book Ali: A Life, reviewed the videos of all Ali's fights and counted that he got hit +200 000 times.

It was Ali's strategy to let his opponents come at him and tire them out so that in later rounds he could win them over. While this strategy might have yielded unprecedented success to Ali's fighting career, it definitely took a toll on his health. Eig says that as far as in early 1971 Ali noticed the first symptoms of brain damage. He was 29 years old at the time. In 1977 he was recommended by his longtime personal doctor Ferdie Parcheco to retire from his boxing career. Ali disregarded this recommendation and continued to fight his opponents in a boxing ring until 1981. A few years after retirement Mohammad Ali was diagnosed with a cluster of symptoms that resemble Parkinson's disease.



Ali's case is a prime example of a Traumatic Brain Injury (TBI). Sometimes referred to as the "silent epidemic", TBI is a leading cause of death and disability among children and young adults with millions sustaining TBI in sports, traffic accidents and military conflicts. TBI often leads to long-lasting neurological deficiencies, memory disturbances, speech irregularities and changes in behavior. The disease has been implicated in various neurodegenerative diseases like chronic traumatic encephalopathy, Alzheimer's disease, and Parkinson's disease.

The primary injury caused by mechanical impact to the brain is caused with accidents that "hit" the head of a patient really hard: American football, fighting sports, road accidents, bomb blasts in military-related activities.

The secondary, and often less talked about, injury occurs gradually as a consequence of destructive cellular and molecular events that follow the primary injury. The cascade of events leads to the widespread atrophy of brain tissue and various neuronal damages. Current treatments for TBI are limited to palliative care and there are no effective strategies to try to mitigate the pathological cascade that leads to neurodegeneration.

The difficulty of developing therapeutic interventions for TBI could be largely attributed to the blood-brain barrier (BBB). BBB is a selective semi-permeable border of endothelial cells that prevent various molecules from flouting from blood to the brain.


BBB is a kind of filtration system that makes sure that the blood that the brain "drinks" is not contaminated with pathogens. Scientists already know some of the biological events and pathways that are implicated in the cascade of molecular events that happen post brain injury, however, they are not able to "send" medication to the brain because the BBB thinks that these molecules are "enemies of the brain". In light of this context, the problem for the scientists becomes this: how does one deliver drugs or molecules that bypass the BBB?


A solution is to use nanoparticles to coat and "hide" therapeutic molecules. A study by Brigham and Women’s Hospital has recently created a nanoparticle drug-delivery system that would carry "genetic scissors" (siRNA - small interfering RNA) through the BBB and interfere with the cascade of events that lead to Alzheimer's disease.

As scientists can not be experimenting and tinkering with actual human brains, the proof-of-principle study was conducted in a mouse model of TBI called the weight-dropped model. The latter model mimics brain injury of closed head injury and accompanying concussion and contusion that is a common type of TBI in humans.


Here is how such experimental animal model is used. An anesthetized mouse is put under a beaker where a weight is dropped on the head of the rodent. The mouse is then taken away and given some time to adjust post-injury. The mouse is then analyzed by various physiological or genetic techniques that are relevant to the study. In the case of the TBI nanoparticle study, such mice were then injected with the genetic scissors that are coated by nanoparticles. Astonishing results followed. The mice in the study recorded 50% smaller concentration of tau proteins (which are thought to be implicated in Alzheimer's disease pathology) than a group that had genetic scissors delivered without the nanoparticle coating. This effect size clearly demonstrates the potential in this type of drug delivery.



After months of experimenting with the right composition of molecules that could constitute the nanoparticle coating, the scientist finally found a way to get through the big brain "wall". This is a big achievement for drug delivery in the development of therapeutics in many diseases. To date over 30 clinical trials involving therapeutics of TBI were unsuccessful in clinical trials. The nanoparticle system is a potential new and working solution. The authors of the study say that they will be looking at novel targets that could use their delivery system. The nanoparticles can potentially be repurposed for treatments of other diseases like Parkinson's disease. If Mohammad Ali was born 40 years later, maybe he would have been able to receive treatment not have had to suffer from the traumas that he has suffered during his prolific career.

The article was prepared by Matas Vitkauskas on behalf of INA

Sources: https://www.researchgate.net/publication/221801332_An_experimental_protocol_for_mimicking_pathomechanisms_of_traumatic_brain_injury_in_mice

https://people.com/sports/muhammad-ali-brain-damage-explored-new-book/

https://advances.sciencemag.org/content/7/1/eabd6889

https://www.medsci.org/v14p0494.htm

https://neurosciencenews.com/nanoparticle-bbb-17515/ Sources of illustrations: https://people.com/sports/muhammad-ali-brain-damage-explored-new-book/ https://www.researchgate.net/publication/221801332_An_experimental_protocol_for_mimicking_pathomechanisms_of_traumatic_brain_injury_in_mice