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Brain Injury Regeneration
Posted on: January 21, 2004

Most people working with brain-injured patients in the field of neurorehabilitation today probably take it for granted that, under the right conditions, some degree of "plasticity" and recovery may be possible. However, the actual notion that recovery of function can be promoted by pharmacologic agents, the transplantation of fetal or stem cell tissues, environmental stimulation, hormonal factors and such, is really a very new idea. Twenty-five to thirty years ago, most neuropsychologists accepted the hypothesis that, in the damaged adult brain especially, after a functional area was lost, there was no possibility of recovery, regeneration, or repair. There is now more debate and more empirical evidence that functional recovery can occur under certain conditions. Not everyone agrees that physiologic repair of the damaged brain or spinal cord is going to occur under all conditions, but it is no longer possible to deny the thousands of laboratory animal and human studies in which some extent of repair and regeneration can be stimulated under the appropriate circumstances. The major focus is upon determining what those factors are and how to apply them to successful repair after degenerative or traumatic injuries to the brain or spinal cord.

Therapies for Brain Injury
After years of research and development in the pharmacology of CNS repair, there are essentially no clinical treatments available to promote recovery of function after traumatic brain injury (TBI). However, considerable effort to develop effective therapies is still needed. In plasticity research there are three areas seeking to promote functional recovery from brain injury. First is the quest for neuroprotective agents to lessen the impact or "shock" of the trauma on the surrounding nervous tissue during the acute phase of the injury. Second is the use of either pharmacologic agents or cell transplantation to enhance neuroregenerative mechanisms after injury. Third, there is the use of behavioral or pharmacologic therapies to encourage "neuroreorganization" (Table below).

Current methods to enhance recovery of function

Method to enhance recovery Description
Neuroprotection Administration of compounds that protect neural tissue from cytotoxic and excitotoxic effects of the injury cascade
Regeneration Administration of trophic factors or transplantation of cells to reestablish normal neural structure
Rehabilitation Using behavioral training or manipulation to stimulate the brain to relearn various tasks
Pharmacotherapy Administrating pharmacological agents to enhance the effect of rehabilitation

Brain "injury" itself is not a monolithic or isolated event. "Brain injury" is a complex cascade of biochemical and morphologic processes of varying duration, each of which may contribute to neuronal death or repair and regeneration. What were once thought to be unrelated biochemical pathways that resulted only in neuronal death now have been shown to be interconnected, and can pave the way for brain repair?

Neural regeneration
Neuroprotective agents act by protecting the brain from secondary injury in the early phase of the trauma. Current research has started to refocus upon what can be done to stimulate the regeneration of neural tissue. Such therapies consist of trophic factor administration-agents that stimulate the repair, regeneration, elongation, and reconnection of damaged axons or dendrites-and transplantation of stem cells, which have the ability to migrate to areas of damage to replace lost neurons and glial cells.
Neurotrophic factors. A class of proteins and peptides showing promise in head injury treatment are those falling into the category of neurotrophic factors that are produced by the brain itself during development and after injury. One problem with the use of trophic factors as therapeutic agents in human patients is that they do not appear to pass through the blood-brain-barrier in sufficient quantity to be clinically effective. Rats given intracerebral or intraventricular administration of brain-derived trophic factor, nerve growth factor, and basic fibroblast growth factor (bFGF), have shown significant functional and morphological recovery after lesions of the nucleus basalis magnocellularis, the septal nucleus, the hippocampus, and the enchorial cortex, among others. Opposite to the neuroprotectants, which had good results with laboratory animals, clinical trial data do not tend to support the use of neurotrophic factors in human patients because of increased mortality in the bFGF-treated groups.
Recovery by replacement. Until only a few years ago, glial cells or embryonic stem cells received scant attention as agents that could facilitate recovery from brain damage. Now, glia have been shown to secrete neurotrophic factors that stimulate sprouting and regeneration, contribute to axonal repair by remyelinating damaged nerve fibers, and modify and contribute to neural transmission in response to brain injury. Recently, investigators have shown that astrocytes in the brain of adult mice can give rise to new neurons in the hippocampus, an area of the brain consistently implicated in memory processing. In the context of developing more effective therapeutic agents to promote functional recovery, it would be advantageous to focus some research upon what effects drugs or stem cell lines might have on the enhancement of the glial response to injury. Such effort would be especially important if glia can be shown to play a role in neurogenesis or regeneration in the adult brain.
In this context, another similar and exciting new area of research is focusing on the use of neural stem cells to repopulate the injured nervous system with cells that have the capacity to develop into a variety of different organs, including brain cells. The initial experiments with these developing cells have proved quite interesting. The recent study showed that when cells from a mouse neural stem cell line were injected into cholinergic basal forebrain areas of mice with fimbria-fornix lesions, these implanted cells were differentiated into a neuronal phenotype that express choline acetyltransferase and the p75 neurotrophic factor receptor.
The bone marrow stromal cells injected into the internal carotid artery after traumatic brain injury in rats were able to enter the brain parenchyma at the site of injury and differentiate into both neuronal- and astroglial-like phenotypes. In addition, rats treated with these stromal cells had improved neurological scores when compared to their injured controls. Although these findings are tantalizing, further long-term survival and sex difference studies need to be performed to determine the long-term effects of these treatments. This cautious approach is needed in light of recent clinical studies using fetal cells in Parkinson's disease patients. In these clinical studies, patients that received fetal cell transplants had either shown no differences from controls or had a greater level of side effects such as dyskinesia. Thus, given the recent negative results of fetal tissue grafts in Parkinson's patients, additional caution may be needed when considering this type of therapeutic because long-term implantation of these cells has not been done in rodents, let alone humans.

A number of researchers have tried to promote reorganization by taking either one of two paths. One path consists of using drugs to enhance synaptic transmission whereas a second uses behavioral training techniques in the hopes of stimulating the brain to restructure. As an historical example, one of the most direct hypotheses of recovery after brain injury is that the replacement of essential neurotransmitters lost because of stroke or injury would be beneficial. Just over 50 years ago, medical researchers administered anti-acetylcholinesterase agents or cholinergic stimulants to human stroke and head injury patients or to monkeys with unilateral lesions of the motor cortex. More recent experiments have employed amphetamine or amphetamine-like substances to alter norepinephrine levels in brain damaged animals. Drugs that deplete central norepinephrine have been shown to impede recovery.
Reorganization by stimulation. In addition to amphetamine, researchers have used other catecholamine and cholinergic agonists. In rats dopaminergic enhancers stimulate recovery after traumatic brain injury. Activating the cholinergic system after TBI using cholinergic agonists or a cholinergic precursor cytidine-5'-diphosphate-choline improves both behavioral recovery of function and biochemical markers of brain activity. From these studies we can assume that pharmacologic manipulation of the major excitatory neurotransmitter systems, when coupled with behavioral training, will improve recovery.
One of the problems with amphetamine is that it is a "dirty" drug that can affect many different neurotransmitter systems. This makes it very difficult to determine what its' specific physiologic effects might be. Nonetheless, it has been repeatedly shown to improve long-term cognitive and motor performance in brain-damaged laboratory animals. One complication with amphetamines is that interaction with environmental stimulation or experience seems to be needed to obtain recovery.
Forced use and recovery of function. In dramatic contrast to the pharmacologic approaches, the recent study demonstrated that behavioral activity alone could improve recovery of function. For example, some stroke patients lose the use of the arm and hand on the side of the body opposite to the injury. They then use their "good" limb as much as possible to compensate for the loss of the affected limb. Recently, the researchers have been able to demonstrate convincingly that if such patients are forced to use the impaired limb, dramatic and sustained recovery can be observed. The technique is simple: the patient's good limb is restrained in a sling or tied behind his or her back, so the only way to accomplish the tasks is to use the affected hand. When forced to do this patients begin to show consistent improvement by "relearning" to use the impaired hand.
It should be noted that there may be critical periods in which this type of rehabilitative method should be avoided because the sensitivity of the injury penumbra to the increased level of activity. Separate studies show that either forced use or environmental stimulation early after injury can worsen the extent of brain damage and in some cases increase the severity of behavioral deficits. This is probably because increased, functional excitation occurring too early in the injury process can lead to excessive release of excitatory neurotransmitters such as glutamate, and this in turn will kill vulnerable neurons.
Neurosteroids and neuroreorganization. As mentioned previously (original article), progesterone and its metabolites are neurosteroids that can act as potent neuroprotectants. They act at a number of sites by inhibiting pathways that are upregulated by TBI, such as the excitatory neurotransmitters and the inflammatory cytokines. During the period immediately after TBI or stroke, progesterone can protect the injured brain from secondary damage, but such treatment in the chronic stage of the injury may not promote additional recovery of function. There are other neurosteroids, such as dehydroepiandrosterone sulfate (DHEAS), which have opposing action to that of progesterone and its GABAergic metabolites. Although progesterone and its metabolites promote inhibition in the CNS, DHEAS can increase the excitatory tone of the brain. DHEAS can also act as an antagonist of the GABAA receptor. DHEAS binding to these sites on the GABAA receptor causes strong inhibition of GABA transmission, thus tilting the tone of brain activity away from inhibition; such changes may be beneficial during the chronic phase of the injury.
DHEAS also stimulates cholinergic transmission by increasing the release of acetylcholine in the hippocampus as measured by in vivo micro dialysis in anesthetized rats. Depressed cholinergic activity has been widely reported in TBI literature. The recovery of cholinergic activity has been linked with improved cognitive and motor performance in a number of experimental brain injury models.

Overall, the injury process is a complex cascade of events that can be influenced dramatically by numerous variables. These variables include sex, age, severity and momentum of injury, hormonal state, and the time of trauma, to name just a few. Additional therapies may include treatments that do not directly affect neural tissue, but instead promote recovery of function by working indirectly by modulating the immune system or on the vasculature to increase blood flow and brain metabolism. Because brain injury is a major public health problem, more attention is now being paid to research in this area. Older paradigms that held that the mature brain is incapable of inherent plasticity and repair are being rapidly replaced by a more optimistic vision of CNS plasticity, which will eventually translate into more effective and enduring treatments and therapies for the "silent epidemic."

Source: Donald G Stein, Stuart W Hoffman; Concepts of CNS plasticity in the context of brain damage and repair; The Journal of Head Trauma Rehabilitation. Jul/Aug 2003. Vol. 18, Iss. 4; pg. 317-341.
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