INTRODUCTION:

TBI is a neurological disorder which represents the root causes of mortality and morbidity among all age groups, caused by road traffic accidents, athletic events, or violence^1,2. TBI is a complex neurological disorder of the brain which is caused by rapid movement within the skull, leading to damage with the symptom of mild to moderate TBI, which includes nausea, headaches, dizziness, amnesia, etc.² Brain damage is now more common than any other disease, including complicated diseases such as breast carcinoma, multiple sclerosis, AIDS and Parkinson’s syndrome³.

According to the Centers for Disease Control and Prevention, traumatic brain injury affects millions of people globally, Over 50 million individuals suffer from TBIs each year and it happens every 15 seconds⁴. In the United States, TBIs were found in 25% of all injury-related fatalities that occurred during 2017⁵. Nonetheless, systematic analysis shows that more than 7.7 million people in the European Union have TBI-related disabilities⁶. In India, as well as in other developing countries, TBI is also leading causes of morbidity and fatality. In India, approx. 1.6 million individual suffers from head injury each year, out of which 0.2 million people die, and 1 million require rehabilitation services at any time. In India, there are an estimated 9.7 million TBI patients, with 16 percent of which they suffer serious TBI⁷. According to subsequent evaluations, increased motor vehicle use is associated with an increase in the TBI rate in people living in developed countries^6,8. The absence of standard reporting and classification in epidemiological studies throughout the world is a major cause of concern. As a result, TBI has been labeled “silent epidemic” for a variety of reasons⁴. Traumatic brain injury is characterized by primary and secondary injury and exerts a severe impact on cognitive, behavioral, psychological, and other health problems. In TBI, the damage is induced by a direct or reversible secondary mechanism. Due to primary insult, there is sudden mechanical damage of the brain tissue that occurs and which cause delayed pathogenic events which collectively mediate widespread neuro-degeneration⁹. As shows in Fig. 1, during the pathogenesis of traumatic brain injury, the primary injury initiates the secondary injury process, which spreads via multiple molecular and cellular mechanisms. Repetitive or chronic TBI induces secondary injury that are linked to an elevated risk of neurodegenerative diseases such as PD, AD and CTE¹⁰.

Fig 1: TBI in progression of neurodegenerative disorders

On the basis of the severity TBI is typically categorized by using the Glasgow coma scale. Mild injury (13-15): In mild TBI, loss of awareness occurs for less than 30 minutes, and post-traumatic amnesia persists not more than 24h. Transient confusion, disorientation, and cognitive dysfunction were also observed in the mild head injury. Moderate injury (9-12): In moderate TBI, loss of consciousness occurs for 30 minutes to 24h, and post-traumatic amnesia persists from one day to 7 days. Severe injury (3-8): In severe TBI, loss of consciousness occurs for more than 24h, and post-traumatic amnesia persists for more than 7 days¹⁰. Development of neurodegenerative disorder is connected with the impact of mild, moderate, severe of TBI¹¹.

Fig. 2: Neurodegenration

Role of Tbi in Induction and Progression of Alzheimer’s Disease:

The prevalence of traumatic brain injury has really been connecting to Alzheimer’s disease, because of that both illnesses share same identical pathology markers like Amyloid beta and hyperphosphorylated tau cumulation¹². With the help of autopsy, certain type of pathological characteristics have been detected in in Alzheimer’s disease where phosphorylated tau observe elevated and both Amyloid beta or transactive response DNA binding protein-43accumulated^13,14. Epidemiological studies have shown that TBI may be a threat factor for AD¹². Diffused axonal injury and beta amyloid accumulation are found in approximately 30% of fatality, that occurred abruptly following a single TBI¹⁵. one of significant study with have strong evidence of an increased Alzheimer’s risk found that older adults who suffered a moderate or severe TBI were 2.3 times more likely to develop the disease than those who had never been injured. Those who had suffered a severe TBI were 4.5 times more likely to develop the disease. Although not all, some investigations also found links among moderate traumatic brain injury and severe injury and an elevated risk of death⁵.

Because of TBI results in bleeding, coagulopathy, inflammatory responses, blood brain barrier instability, edema formation and vasospasms also observed in Alzheimer’s disease¹⁶. Traumatic brain injury could be viewed both as a cause and as a model to study some pathological aspects of Alzheimer’s disease, such as the build-up of amyloid plaques and Tau proteins. Both TBI and AD are associated with tau pathology and Amyloid beta even though their etiologies are different. Cerebrovascular disease (CVD) can also be caused by Amyloid beta and tau. Though beta amyloid and Tau are both found to cause cerebral vascular disease^17-20. Cerebrovascular events are the root cause of many neurological diseases²¹, endothelial cell injury affects cerebral blood flow (CBF). Endothelial cell injury decreases circulatory supplies impair the integrity of the blood-brain barrier and finally goal is to influence abnormalities of the brain and destruction of an endovascular cell²². Moreover, diseases like high blood pressure, dyslipidemia, and hyperglycemia result in the destruction of the brain endothelium in TBI and increased the risk of neurological illnesses like AD²³.

Role of TBI In Induction And Progression of Depression:

It has been proposed that traumatic brain damage is a factor in the development of depression and other disorders. Over 15 years after the injury occurrence, the morbidity of depression following TBI was reported to be higher than in non-TBI groups²⁴.

The post-TBI depression pathogenesis is immensely complicated. Individuals who have suffered from a traumatic brain injury experience a progressive loss of brain tissues in the frontal cortex regions, sometimes years after the injury²⁵. Several investigations revealed that TBI lowers deep gray matter in the cerebellum and cerebral cortex^26,27. According to the pilot study, grey matter loss may have a role in developing post-traumatic brain injury depression and there is evidence that damages may cause the beginning of depression in the dorsolateral, frontal, and temporal lobes, along with left basal ganglia after TBI. Frontal lobe-basal ganglia pathways and frontal ascending dopaminergic pathways have been involved in studies of depression following TBI^28,29.

After a TBI, cytokines are elevated, resulting in persistent inflammatory responses, which could be a risk factor for depression. Interleukin-1,6 and TNF alpha levels in CSF^30,31 and plasma³² increase significantly after Traumatic brain injury, according to research, which was related to depression. Another etiology concept for depression is the monoamine hypothesis, which claims that a decrease in MAO neurotransmitters like dopaminergic, serotonin, and adrenaline could induce depression. Failure of the dopaminergic system will reduce several features of distress and motive while activating the pathways that mediate sadness and anxiety^33,34. Due to TBI, inhibitory amino acids like glutamate could induce damage to neurons and promote cell death and Noradrenaline is considered to minimize damage induced by glutamate and prevents cells from death following TBI³².

Role of Tbi In Induction And Progression Of Chronic Traumatic Encephalopathy:

Chronic traumatic encephalopathy (CTE) usually affects those with a history of repetitive closed head injury, particularly common in professional boxers³⁵. Also, the fact that CTE is caused by repeated trauma. According to some studies, even a single traumatic brain injury is enough to trigger it³⁶. CTE, in general, causes cognitive, behavioral, and physical impairments. Distress, restlessness, anger, impaired memory, and increased suicidal tendencies are common early signs³⁷.

Just a minor impact can cause severely damage to axons and alter the permeability of the membrane resulting in calcium influx³⁸. As a result of caspases and calpains, tau is phosphorylated, misfolded, shortened, and aggregates are formed. Microtubules and neurofilaments are also damaged, causing cytoskeletal failure. In the acute setting, head injury stimulates microglia, causing them to generate toxic amounts of cytokines, immunological mediators, chemokines, excitotoxins, including glutamate, aspartate, and quinolinic acid involved. Phosphatase is inhibited by these excitotoxins, resulting in excessive tau hyperphosphorylation, microtubule malfunction and neurofibrillary tangles are deposited in certain parts of the brain³⁹.

In 40-50% of cases, β-Amyloid aggregates are found and are closely linked with mortality rate. Beta-amyloid as diffuse plaques in low densities are generally reported in chronic traumatic encephalopathy cases⁴⁰. In around 20% of instances, synuclein-positive Lewy bodies are linked with CTE and are related to the patient's age at death⁴¹. Additionally, the TDP-43 was found to be extremely prevalent in ten out of twelve patients of CTE. The inclusions are generally detected on perivascular, or periventricular surfaces in the early stages. The aggregation of TAR DNA-binding protein in chronic traumatic encephalopathy co-localizes with p-tau inclusions in neurons to some level. A number of cellular transcripts, including tau and β-synuclein, are bound by TDP-43 and instability of this protein might contribute to a few of the diseases associated with it⁴².

Role of Tbi In Induction and Progression of Amyotrophic Lateral Sclerosis Induced:

The condition is identified by degeneration of motor neurons in both upper and lower limbs, which negatively influences sufferers' standard of living and significantly enhances the responsibility of parents and the community⁴³ and risk of ALS increased by 1.38-times. Severe TBI had a 69% higher risk of developing ALS in the brains of sportspersons (football and boxing) who had periodic brain injuries^42,44. The severity of brain injury may increase amyotrophic lateral sclerosis.

Due to head injury blood brain barrier disrupt, which is permeable to numerous solutes containing toxic substances. Researchers have postulated that disruption of the blood brain barrier may contribute to the pathogenesis of ALS^45,46. The study by using fly models in amyotrophic lateral sclerosis discovered that Traumatic brain injury could trigger stress granule generation in the brain, which increases motor system dysfunction⁴⁷. It has been shown that stress-granule formation is directly related to disruptions in nucleocytoplasmic transport which is a hallmark of C9orf72 ALS, which suggests that there may be an significant overlap between TBI and ALS. In patients with ALS, head injury provokes TAR DNA protein pathology, a neuropathological hallmark lesion of the brain⁴⁸. The hallmark of CTE is the widescale accumulation of TAR DNA protein and Tau, which is also observed as pathological biomarkers of amyotrophic lateral sclerosis^40,49.

TDP-43 has shown to be especially susceptible to disintegration of protease in a variety of neurotoxicity circumstances including TBI, which might also exacerbate loss-of-function consequences in afflicted cells. As a result, we suggest that TBI may play a role in the breakdown of proteostasis observed in ALS sufferers, resulting in irreversible proteotoxic stress⁴⁸.

Role of Tbi In Induction And Progression of Epilepsy:

Traumatic brain injuries are the third leading cause of epilepsies, which are caused by damage to the brain parenchyma either directly or indirectly^50,51. The mitochondrial dysfunction has been known to be a cause of oxidative stress and neurodegenerative processes that contribute to Post-traumatic epilepsy⁵². PTE is among the most commonly occurring and the most severe outcomes of traumatic brain injury in study showed than 50% of people was developed epilepsy after a severe TBI⁵¹.

An immediate post-traumatic seizure is likely to occur due to the effect of injury stimulating brain tissue with a decreased threshold for seizures⁵⁰. Various secondary effects of head trauma can contribute to early post-traumatic seizures, such as cerebral oedema, cerebral contusion or incision, intracranial hemorrhage, extracellular ion alterations, uncontrolled production of excitatory neurotransmitters like glutamate and free radical destruction⁵³. Late seizures are assumed to signal persistent structural changes in the brain caused by synaptic and neuronal loss and rewiring. In numerious humans and in animal models, increased excitatory connectivity and decreased GABAergic inhibition contribute to injury-induced epileptogenesis⁵⁴.

Following TBI, a rise in exogenous glutamate generally causes excitotoxicity in the brain. This is absorbed by astrocytes and transformed into glutamine, which will then be transferred out onto cells as an extra energy source under physiological conditions⁵⁵. On the other hand, a high level of glutamate overwhelms astrocytes' function that eliminates glutamate out from extracellular fluid, resulting in a massive influx of calcium or sodium and also the efflux of potassium⁵³. Because of the ion imbalance, the postsynaptic cell membrane hyperpolarization occurs, that leads to a rise in excitatory postsynaptic potential. TBI-induced changes in calcium signaling, NOS, proteases, and lipases are activated, resulting in cell signaling cascades linked with excitotoxicity and apoptosis⁵⁶. An increase in the level of nitric oxide disrupts the mitochondrial function due to loss of energy and produce oxidative stress in neurons. Changes in mitochondrial function lead to activation of caspases by which cyt.C is activated, resulting in apoptosis due to inflammation^54,57. TBI compromises the integrity of mitochondria by releasing reacting oxygen species and reacting nitrogen species that destroy membrane lipids, proteins, deoxyribonucleic acid and inhibits the production of transporters of glutamate like GLT-1 and GLAST, resulting in excitotoxicity of cells^58,59.

Role of Tbi In Induction and Progression Of Parkinson’s Disease:

Clinical studies indicate that athletes, boxers, and ex-military personnel who have been previously concussed have a greater chance of having Parkinson’s disease, which occurs years after the initial TBI injury^10,60-62. Moderate to severe TBI have an 83% increased risk of Parkinson’s disease; those with mild TBI have a 56% risk⁶³. The risk of developing PD was 1.5 times greater for patients with mild TBI and 1.8 times greater for those with severe TBI⁶⁴. In US, the majority of TBIs are due to men and they are also twice as likely to develop Parkinson’s disease^65,66.

In the post-TBI phase, neurodegeneration occurs due to the transient permeabilization of the BBB, which allows peripheral macrophages to infiltrate. Specifically neuronal, microglial, and astrocyte alpha-synuclein depositions are prevalent. It culminates in the progression of neurodegeneration that ultimately results in PD⁶⁷. In PD, the hallmark changes are loss of the neurons in the pars compacta of the substantianigra, increase in reactive astrocytes and infiltrating macrophages, and the appearance of phagocytic microglia. There is an apparent overlap between pathological features of prodromal Parkinson’s disease and those induced by TBI. This may cause TBI to accelerate the onset of prodromal Parkinson’s disease^68,69. In an overexpressed state, α-synuclein disrupts the cell membrane of dopaminergic neurons alpha-synuclein may represent a pathogenic link between chronic effects of TBI and symptoms of Parkinson’s disease, as shown by upregulation and anomalous cumulation of alpha-synuclein in substantianigra of rats that are exposed to chronic TBI⁷⁰.

Table: Neurodegenerative Disorders Shares Common Pathophysiology with Traumatic Brain Injury

S. No.	Neurodegenerative Diseases	Neuropathology Markers Common With TBI
1	Neurodegenerative Parkinson’s	Dopaminergic neuron, Alpha-Synuclein, Tyrosine Hydroxylase
2	Chronic traumatic encephalopathy	Calpain and Caspase, Beta-amyloid, TNF-α
3	Epilepsy	Excitotoxicity and Neuroinflammation
4	Amyotrophic lateral sclerosis	TDP -43, Tau
5	Alzheimer's	Amyloid-β and Hyperphosphorylated Tau
6	Depression	MOA, Serotonin, Dopamine, Norepinephrine, Cytokine

CONCLUSION:

TBI survivors with prolonged symptoms show structural and functional impairment.TBI may result in extensive neuronal loss, depending on the severity and impact of trauma. An accelerated neurodegenerative process and an increased probability of PD, AD and illness of the motor neurons have been identified in some studies following moderate-to-severe TBI. Several approaches show a strong correlation between TBI secondary injury and various neurodegenerative diseases involving oxidative stress and numerous neuroinflammation diseases. It appears that oxidative stress plays a crucial role in both TBI and neurodegeneration by causing neuro-inflammation and glutamatergicexcitotoxicity. Due to TBI, axonal damage and dysfunctional axonal transport may lead to a long-term accretion of a number of key axonal proteins, including APP, synuclein, Tau, TDP-43, and related peptides that tend not to accumulate in overhead concentrations within axons in normal conditions. As a result, Aβ NFTs, Aβ plaques and other assorted bodies or inclusions in the brain can be processed and accumulated. The presence of such malfunctioning peptides after TBI indicates a continual pathological process due to impaired transport.

FUTURE ASPECTS:

It will be necessary to elucidate the mechanisms involved in pathological protein dynamics observed in patients with TBI and the reasons why TBI increases the risk of neurodegeneration. The molecular mechanisms of molecular cascades that underlie pathological protein dynamics will be examined in patients with TBI, with the aim of identifying the reasons for increased neurodegeneration risk due to the injury. In order to develop neuroprotective strategies that will minimize the long-term effects of moderate/severe TBI, an in-depth understanding of these mechanisms is essential.

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Received on 06.02.2023 Modified on 11.09.2023

Research J. Pharm. and Tech 2024; 17(4):1909-1915.

DOI: 10.52711/0974-360X.2024.00303