Traumatic brain injury and chronic neuroinflammation

Traumatic brain injury (TBI) even in it's milder forms can initiate a process of chronic neuroinflammation that causes a range of chronic neurodegenerative disorders. The authors of a paper just published in Neuropsychiatric Disease and Treatment detail the secondary injury cascades that exacerbate the damage and can lead to chronic traumatic brain injury.

"Mild TBI, sometimes referred to as concussion, is the most prevalent TBI. Although TBI has been traditionally considered an acute injury, accumulating clinical and laboratory evidence has recognized the chronic pathology of the disease. Indeed, TBI can manifest many symptoms of neurodegenerative disorders, such as Parkinson’s and Alzheimer’s disease...Accumulating laboratory and clinical evidence has implicated neuroinflammation in both acute and chronic stages of TBI, suggesting this secondary cell death pathway may be the key to the disease pathology and treatment..."

Neuroinflammation in traumatic brain injury stands out as a target of inquiry:

"Here, we focus on neuroinflammation, which closely manifests immediately after TBI onset, and equally important, it persists in the chronic stages of the disease, making it an appealing target for understanding TBI pathology and its treatment."

Mild traumatic brain injury may cause a variety of symptoms to persist

Clinicians need to be alert to a range of possible symptoms long after the original injury.

"Most patients fully recover in a couple hours or days, although it may take a couple of weeks. However, depending on the severity of the injury, there are some cases in which victims do not recover and the symptoms persist for years....Clinical manifestations of mild TBI consist of a combination of physical and neuropsychiatric symptoms, which include behavioral and cognitive disorders...Of the physical symptoms of TBI, headaches are the most common, with around 25%–90% of post–mild TBI patients reporting it. Dizziness and nausea are other common symptoms, along with fatigue, sleep disruption, hearing problems, and visual disturbances. As a result of damage to the frontal or temporal lobe, TBI patients are also prone to seizures, which may present a challenge for diagnosis and treatment (ie, differential diagnosis between TBI and epilepsy)."

Chronic cognitive and behavioral disorders from mild traumatic brain injury

The cascade of neurodegenerative effects stemming from mild traumatic brain injury are tragically life altering.

"Cognitive disorders after TBI primarily include attention deficit, memory problems, and executive dysfunction. Attention deficit is very common and interferes with other functions, making daily tasks harder than before...These include irritability, mood changes, aggression, impulsivity, self-centered behavior, and poor persistence. Other symptoms related to TBI are depression (sadness, low energy and motivation, not liking oneself, hopelessness), anxiety, and posttraumatic stress disorder. In addition, as noted earlier, TBI may increase the risk of developing Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative diseases in the long term."

Primary and secondary waves of injury

Both short and long term cascades of damage occur when the brain is subject to trauma.

"The initial insult first leads to a primary injury caused by the mechanical damage from shearing, tearing, and/or stretching of neurons, axons, glia, and blood vessels...The primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes. This occurs within seconds to minutes after the traumatic insult and can last for days, months, or years. It often leads to progressive neurodegeneration and delayed cell death, exacerbating the damage from the primary injury. The secondary wave is mainly detected in the injury site and surrounding tissue, although neurodegeneration in brain areas located far from the primary impact has recently been recognized...

The secondary wave consists of excitotoxicity, oxidative stress, mitochondrial dysfunction, blood–brain barrier (BBB) disruption, and inflammation. All these processes contribute to neurological deficits separately, but at the same time, these cell death processes interact, worsening the progressive outcome of TBI."

Excitotoxicity in traumatic brain injury

Substances released by damaged neurons cause brain cells to be stimulated to death.

"...injured nerve cells secreting large amounts of intracellular glutamate into the extracellular space...overstimulates the AMPA and NMDA receptors of surrounding nerve cells. These receptors stay activated, allowing an influx of sodium and calcium ions into the cell. The high concentration of calcium ions in the cytosol leads to the activation of protein phosphatases, phospholipases, and endonucleases. Eventually, the DNA is fragmented, and structures and membranes of the cell are deteriorated. This results in cell death through a hybrid form of apoptosis and necrosis. The overstimulation of glutamate receptors also results in the increased production of nitric oxide, free radicals, and pro-death transcription factors."

ROS in traumatic brain injury

A damaging increase in free radical reactive oxygen species (ROS) and reactive nitrogen species (RON), which are normally kept at a low level in the brain by antioxidants and enyzmes, also contributes to neuronal cell death.

"After TBI, a significant increase in ROS and impairment of antioxidants that lower the levels is seen. When the generation of ROS/RON is too large, it leads to major cell dysfunction, as its oxidative capabilities damage all biomolecules. ROS cause lipoperoxidation of the cell membrane, which results in the dysfunction of many structures and organelles, such as the mitochondria and oxidizing proteins that affect membrane pores. It may also fragment DNA, causing mutations. ROS are also related to the infiltration of neutrophil, which induces an inflammatory response that, in turn, increases the generation of ROS. Overall, oxidative stress cascade results in large neuronal cell death."

Mitochondrial dysfunction in mild TBI

Mitochondrial dysfunction, typically a contributing factor to neurodegeneration in general, also plays a role in neuronal cell death and chronic loss of brain function following traumatic brain injury.

"After TBI, the stabilizing mechanisms of levels of ROS become impaired, resulting in increased concentrations. Lipid peroxidation-mediated oxidative damage to the mitochondrial membrane negatively affects its structure and function. The mitochondria also works as a calcium ion buffer, releasing and absorbing the ions as needed to maintain homeostasis. However, when the calcium ion load becomes too large from excitotoxicity, the function of the mitochondria becomes impaired. The mitochondrial permeability transition pore, associated with the mitochondrial inner membrane, is a calcium ion-dependent pore. With the excess calcium ions, the pore stays active, disrupting the mitochondrial membrane potential. Without a membrane potential, the mitochondria is unable to produce ATP, and the ATP synthase may actually consume ATP instead of producing it. With mitochondrial break down, toxins and apoptotic factors are released into the cell, activating the caspase-dependent apoptosis. This causes the cell to commit suicide."

Blood-brain barrier disruption

Loss of blood brain barrier (BBB) integrity also contributes to brain cell death following TBI.

"BBB dysfunction is related to neuronal cell death and cognitive decline and limits the effectiveness of therapies. Its dysfunction triggers many other secondary injuries, including cell death, oxidative stress, and inflammation, causing the brain to swell, with higher intracranial pressure and ischemia. The primary injury disrupts the tight junctions, allowing an influx of peripheral immune cells and circulating factors (albumin, thrombin, and fibrinogen). These events affect the interaction between BBB endothelial cells and astrocytic glial cells, further contributing to the effects of BBB dysfunction by increasing its permeability. One of the underlying mechanisms regarding BBB dysfunction after TBI is the up-regulation of protein matrix metallopeptidase 9 (MMP-9). This digests the tight junctions, disrupting its proper function. BBB breakdown also allows an influx of larger molecules such as leukocytes that increase the osmotic force in the brain. This results in edema and higher intracranial pressure, which are directly related to ischemia and further cell death."

 Neuroinflammation, the 'big enchilada'

Brain inflammation may be the leading contributor to accelerated loss of brain cells in most forms of neurodegeneration. In traumatic brain injury it is triggered immediately after impact and can continue for many years.

"After the initial injury, an endogenous inflammatory response is triggered to defend the injury site from invading pathogens and to repair the damaged cells. The complement is activated to perform these functions and recruits inflammatory cells into the intrathecal compartment. The activation of the complement is also accompanied by the infiltration of neutrophils, monocytes, and lymphocytes across the BBB. These secrete prostaglandins, free radicals, proinflammatory cytokines, and other inflammatory mediators that, in turn, up-regulate the expression of chemokines and cell adhesion molecules. This results in immune cells and microglia mobilizing into the brain parenchyma."

While the microglial cells perform important positive functions that limit damage and sequester the injured tissue, they fire up neuroinflammation by over-reacting. This is particularly true of the M1 phenotype of glial cells.

"...microglial activation in TBI is excessive, and proinflammatory cytokines such as tumor necrosis factor (TNF)- , IL-1 , IL-6, IL-12, and interferon are released. The up-regulation of these cytokines increases the permeability of the BBB by higher expression of cell adhesion molecules in the endothelial cells and by an increased production of chemokines. This results in an increased inflammatory response. Sustained microglial activation also produces neurotoxic molecules and free radicals, which lead to other mechanisms of secondary cell death...In addition, activated microglial cells increase the expression of major histocompatibility complex class II (MHCII ), which is directly correlated to neurodegeneration."

Astrocytes too exert beneficial effects by increasing brain-derived neutrophilic factors (BDNF) and regulating extracellular glutamate to reduce excitotoxicity. However...

"...when the presence of astrocytes is too large and they become overactivated, it can lead to detrimental effects in the brain. The astrocytes secrete inhibitory extracellular matrix, building a dense physical and chemical barrier surrounding the injury site (glial scar), which encapsulates and isolates the axons. This protects the remaining healthy brain from the neurotoxic environment of the injury site, but it also interferes and prevents the regeneration and repair of the damaged tissue."

What to do?

A rational treatment plan should include the various remedial measures that target all of these processes:

• Wind down glutamate excitotoxicity
• Oppose oxidative stress
• Support mitochondrial function
• Help repair the blood-brain barrier
• Calm neuroinflammation

These processes play a role in neurodegeneration from other causes besides traumatic brain injury. The clinician should have a repertoire of remedial measures at hand to address them. Past and future posts report on advances in treatment. Calming neuroinflammation plays a premiere role."

"It takes considerably more time for the inflammatory cells to reach the injured brain and contribute to the secondary cell death damage than it takes other secondary death mechanisms, such as glutamate excitotoxicity. This delayed onset provides an extended window of opportunity in which treatments can be administered, greatly increasing the chances of a successful intervention and preventing further damage."

One cardinal point must be kept in mind: there is a beneficial 'housecleaning' side to neuroinflammation so antiinflammatory therapies should not be overdone.

"Immune cells, astrocytes, cytokines, and chemokines are all necessary components for brain repair, and it is their excessive levels that contribute to the secondary cell death damage in TBI...When considering treatments for neuroinflammation in TBI, it is important to note that inflammation has both beneficial and detrimental effects. Prior studies have shown that high doses of antiinflammatory agents actually lead to worse outcomes. In addition to inhibiting the detrimental effects of neuroinflammation, these robust treatments may also retard the beneficial ones."

Judicious application of natural anti-inflammatory agents to minimize side-effects along with other measures guided by objective measurements is a standard for treating traumatic brain injury that can be applied to other neurodegenerative disorders as well.