Tip:
Highlight text to annotate it
X
Slide 1: This is the second part of the series on traumatic
brain injuries. Today, the discussion will be on the current therapies for traumatic
brain injuries and their limitations. Slide 2:
To understand the therapies we must first understand the mechanism of the injury. As
you can see on the figure, glutamate is normally taken up by astrocytes, converted into glutamine
and secreted to neurons as an alternative energy source. However, damage to the neurons
leads to excessive release of glutamate, a process known as excitotoxicity.
Thus, glutamate binds to neuronal receptors, such as NMDA, inducing the influx of Ca2+
and Na+ and the efflux of K+. This ion imbalance causes depolarization of the cell membrane
and excessive calcium influx results in mitochondrial dysfunction, less production of ATP, energy
failure and eventual cell death. Lack of mitochondrial integrity also causes it to release reactive
oxygen species and nitric oxide species which together cause the oxidative stress that damages
membrane lipids, proteins, and DNA. Furthermore, free Ca2+ activates several enzymes, such
as caspases, which contribute to DNA fragmentation and cell apoptosis. Other calcium-activated
enzymes (eg calpains) disrupt the axon’s cytoskeletal filaments, thus impairing axonal
transport and function. Hypoxia or ischaemia lead to a shift to anaerobic
metabolism by astrocytes, producing lactate, which causes the cells to swell and results
in brain oedema. During the injury glial cells, microglia & astrocytes
are activated and undergo several morphological and molecular changes. Together with fibroblasts,
these cells form the glial scar, which impairs axonal regrowth. Microglia accumulate and
phagocytose the debris from dying cells. Glial cells secrete inflammatory cytokines, neurotrophins
and chemokines that stimulates the infiltration of neutrophils and monocytes to the brain.
Thus the BBB integrity is further impaired leading to increased extracellular fluid that,
combined with cell swelling, leads to brain oedema and increased ICP.
Slide 3: The classic drugs that have already been tested
are such as nootropic drugs that increase cognitive ability, Ca2+ channel antagonists
and vitamins such as magnesium. Drugs that are currently under clinical trials and hold
great promise are like erythropeitin and new experimental procedures are such as use of
laser technology for cell regeneration, hypothermia or combinatory therapy.
Slide 4: Cerebrolysin is a classic example of a drug that has been used in many neurological
diseases. It can easily cross the BBB. Additionally, it behaves like neuron growth factor offering
many advantages to the cell such as protection against apoptosis & necrosis and stimulating
axonal and dendritic growth. Slide 5: Other drugs currently in use are
musculo tropic vasodilators which aim to increase the blood flow to the brain. Vinpocetine enhances
vasodilation and reduces mitochondrial dysfunction. It is currently being used in TBI patients.
Gingko Baloba, a plant extract, is a best seller presumed to have many neurologic benefits
and papaverine, a derivative of ***, is topically applied to blood vessels to improve
neurological outcome and reduce vasospasms especially in patients with sub arachnoid
hemorrhage Slide 6: Promising drugs now include progesterone,
erythropoietin and tranexamic acid. Progesterone is synthesized by oligodendrocytes and has
receptors on neural cells. It reduces glutamate toxic effects, cell death, and inflammation.
It also regulates expression of aquaporin, which might be important in brain oedema.
It has shown some benefits in three randomised trials, with a further two large phase 3 trials
underway Erythropoietin is a hormone that stimulates
haemopoiesis. It also reduces apoptosis, inflammation, oxidative stress, and excitotoxic effects.
Its receptors are up regulated in the brain after injury and it easily crosses the BBB.
It was found to decrease lesion volume and brain accumulation of leucocytes while promoting
angiogenesis and neurogenesis and improving motor and cognitive function. It has a long
half-life but increased risk of thrombotic events. However, Clinical trials are underway
in US & Australia. Slide 7: Amongst the many failed drugs are
those targeting single pathways such as glutamate antagonists, ca2+ channel antagonists like
nimodipine , vitamins like magnesium that actually increased mortality of patients and
antioxidant. An example is pegylated Superoxide dismutase to increase its half-life.
Slide 8: New procedures are such as local hypothermia, decompressive craniotomy and
transplantation. Briefly speaking, though most of this methods were found to be beneficial
in animal models, in humans the results vary. They are therefore under continuous trials.
Transplantation was also found to be technically challenging since only 0.01% of cells actually
get engrafted in the brain. Slide 9:
In conclusion, we have reviewed the secondary mechanisms of brain injury and current & developing
therapies. Unfortunately, most drugs have failed, this is partly due to the focus on
single pathophysiology. Still Erythropoeitin, progesterone & transexamic acid hold great
promise. New therapies also involve use of combination therapy and comparative effectiveness
whereby differences in processes and patients can be related to outcome.