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Background: Traumatic brain injury (TBI) has been reported as a risk factor for brain cancer development. However, the magnitude of the impact of TBI on systemic cancer development has not been clarified., Methods: A retrospective longitudinal cohort study was conducted using the Taiwan Longitudinal Health Insurance Database between January 2000 and December 2011. A total of 35,306 patients were initially enrolled, and 14,795 patients with mild TBI and 14,795 patients with moderate/severe TBI were matched using the National Health Insurance Research Database in Taiwan. The Cox proportional hazard regression model was used to estimate the hazard ratio (HR) of TBI adjusted for potential confounding factors., Results: After matching, the results showed that patients with moderate/severe TBI had a high mortality rate (17.7% vs. 10.4%) and shorter time interval from TBI to death (mean 3.6 years vs. 5.8 years). No differences were observed in cancer incidence (4.1% vs. 4.1%) or risk factors for mortality between mild and moderate/severe TBI patients. However, patients aged between 46 and 55 years, female patients, and patients with pre-existing renal disease had a significant higher cancer incidence risk in moderate/severe TBI compared with mild TBI patients. The top 15 most common cancers showed that mild TBI patients had a higher percentage of head and neck cancer. The overall mortality rate in all TBI patients diagnosed with cancer was about 50%, and the cancer-specific mortality is approximately 85% in death of TBI patients with cancer., Conclusions: We concluded that the incidence risk of a new cancer diagnosis and mortality risk of TBI patients with cancer between the mild TBI and moderate/severe TBI patients were not significantly different., (© 2022. The Author(s).)

Background: Ceftriaxone is a β-lactam antibiotic used to treat central nervous system infections. Whether the neuroprotective effects of ceftriaxone after TBI are mediated by attenuating neuroinflammation but not its antibacterial actions is not well established., Methods: Anesthetized male Sprague-Dawley rats were divided into sham-operated, TBI + vehicle, and TBI + ceftriaxone groups. Ceftriaxone was intraperitoneally injected at 0, 24, and 48 h with 50 or 250 mg/kg/day after TBI. During the first 120 min after TBI, we continuously measured heart rate, arterial pressure, intracranial pressure (ICP), and cerebral perfusion pressure. The infarct volume was measured by TTC staining. Motor function was measured using the inclined plane. Glutamate transporter 1 (GLT-1), neuronal apoptosis and TNF-α expression in the perilesioned cortex were investigated using an immunofluorescence assay. Bacterial evaluation was performed by Brown and Brenn's Gram staining. These parameters above were measured at 72 h after TBI., Results: Compared with the TBI + vehicle group, the TBI + ceftriaxone 250 mg/kg group showed significantly lower ICP, improved motor dysfunction, reduced body weight loss, decreased infarct volume and neuronal apoptosis, decreased TBI-induced microglial activation and TNF-α expression in microglia, and increased GLT-1 expression in neurons and microglia. However, the grades of histopathological changes of antibacterial effects are zero., Conclusions: The intraperitoneal injection of ceftriaxone with 250 mg/kg/day for three days may attenuate TBI by increasing GLT-1 expression and reducing neuroinflammation and neuronal apoptosis, thereby resulting in an improvement in functional outcomes, and this neuroprotective effect is not related to its antibacterial effects., (© 2021. The Author(s).)

Background: The aim of this study was to investigate whether AMN082 exerts its neuroprotective effect by attenuating glutamate receptor-associated neuronal apoptosis and improving functional outcomes after traumatic brain injury (TBI)., Methods: Anesthetized male Sprague-Dawley rats were divided into the sham-operated, TBI + vehicle, and TBI + AMN082 groups. AMN082 (10 mg/kg) was intraperitoneally injected 0, 24, or 48 h after TBI. In the 120 min after TBI, heart rate, mean arterial pressure, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were continuously measured. Motor function, the infarct volume, neuronal nitrosative stress-associated apoptosis, and N-methyl-D-aspartate receptor 2A (NR2A) and NR2B expression in the pericontusional cortex were measured on the 3rd day after TBI., Results: The results showed that the AMN082-treated group had a lower ICP and higher CPP after TBI. TBI-induced motor deficits, the increase in infarct volume, neuronal apoptosis, and 3-nitrotyrosine and inducible nitric oxide synthase expression in the pericontusional cortex were significantly improved by AMN082 therapy. Simultaneously, AMN082 increased NR2A and NR2B expression in neuronal cells., Conclusions: We concluded that intraperitoneal injection of AMN082 for 3 days may ameliorate TBI by attenuating glutamate receptor-associated nitrosative stress and neuronal apoptosis in the pericontusional cortex. We suggest that AMN082 administration in the acute stage may be a promising strategy for TBI.

Background: To date, cardiac dysfunction after traumatic brain injury (TBI) has not been consistent. In this study, we hypothesized that TBI may play a role in the development of new-onset cardiac dysfunction in healthy experimental rats., Materials and Methods: Anesthetized healthy male Sprague-Dawley rats were divided into two groups: a sham-operated control group and a TBI group. The brain was injured with 2.4 atm percussion via a fluid percussion injury model. During the 120 min after TBI, we continuously measured brain parameters, including intracranial pressure (ICP) and cerebral perfusion pressure (CPP), and cardiac parameters, such as heart rate (HR), inter-ventricular septum dimension (IVSD), left ventricular internal dimension diastole (LVIDd), end-diastolic volume (EDV), ejection fraction (EF), fractional shortening (FS), and LV mass diastole (LVd mass) by cardiac echo. On days 1, 3, 7, and 14 after TBI, the brain damage volume was evaluated with triphenyltetrazolium chloride; the physiological parameters of the heart, including HR, IVSd, LVIDd, EDV, EF, FS, and LVd mass, were evaluated with cardiac echo; the morphology of cardiomyocytes was examined by hematoxylin and eosin (HE) and Masson trichrome staining; and the biomarkers of cardiac injury troponin I and B-type natriuretic peptide (BNP) were also examined., Results: Compared to sham-operated controls, the TBI groups had higher ICP, lower CPP, and higher brain neuronal apoptosis and infarction contusion volume. The impact of TBI on heart function showed hyperdynamic response trends in IVSd, LVIDd, EDV, EF, FS, and LVd mass within 30 min after TBI; however, EF and FS exhibited eventual decreasing trends. Simultaneously, the values of the biomarkers troponin I and BNP were within normal limits, and HE and Mass trichrome staining revealed no significant differences between the sham-operated control group and the TBI group., Conclusions: Our results suggest that TBI due to 2.4 atm fluid percussion injury in healthy experimental rats may cause significant damage to the brain and affect the heart function as investigated by cardiac echo but not as investigated by HE and Masson trichrome stainings or troponin I and BNP evaluation.

Background: High cholesterol has been correlated with a greater risk of cerebrovascular diseases. Whether pre-existing high cholesterol exacerbates traumatic brain injury (TBI), and whether treatment with the cholesterol-lowering agent simvastatin has neuroprotective effects, especially anti-neuroinflammatory effects, after TBI are not well investigated., Methods: Five-week-old male Sprague-Dawley rats were fed a high-fat diet for 8 weeks to induce hypercholesterolemia. Anesthetized male Sprague-Dawley rats were divided into 5 groups, including the sham-operated control, TBI control, and TBI with simvastatin treatment (4 mg/kg, 10 mg/kg, or 20 mg/kg) groups. Simvastatin was intraperitoneally injected at 0, 24, and 48 hours after TBI. Motor function was measured using an inclined plane. Neuronal apoptosis (maker Neu-N, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling), tumor necrosis factor-α expression in microglia (marker OX42) and astrocytes (marker glial fibrillary acidic protein), and Tumor necrosis factor-alpha receptor (TNFR) 1 and TNFR2 expression in neurons in the ischemic cortex were investigated using an immunofluorescence assay. All of the parameters were measured on the third day after TBI., Results: TBI significantly increased the serum levels of cholesterol. The TBI-induced motor deficit was significantly attenuated by 4, 10, and 20 mg/kg simvastatin therapy on the third day after TBI. TBI-induced neuronal TNFR1 activation and apoptosis, as well as tumor necrosis factor-α expression in astrocytes in the ischemic cortex, were significantly attenuated by simvastatin, particularly when 20 mg/kg was administered. Simultaneously, the serum cholesterol remained high despite simvastatin treatment., Conclusions: The neuroprotection effects of simvastatin on the pre-existing hypercholesterolemia during TBI in rats may be related to its anti-neuroinflammatory effects but not to its cholesterol-lowing effects., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Previous studies have indicated traumatic brain injury (TBI) as a risk factor for stroke and myocardial injury. Whether TBI increases new onset of major adverse cardiovascular and cerebrovascular events (MACCE) is not well established., Methods: Patients with a diagnosis of TBI from 2000 to 2012 were 1:2 age-, sex-, and age-adjusted comorbidities matched with normal population cohorts. The MACCE, which included coronary artery disease, heart failure and arrhythmia, ischemic and hemorrhagic stroke, and death, was defined as one inpatient admission with MACCE diagnosis. The maximum follow-up duration to MACCE after the initial TBI diagnosis was 5 years. The baseline comorbidities before TBI, including hypertension, diabetes mellitus, renal disease, and liver disease, also were considered to estimate the risk of MACCE., Results: In total, 16,211 patients with TBI and 32,422 people from the control group were enrolled in the current study. Our results showed that patients with TBI had a 2.77-fold risk of MACCE, 1.72-fold risk of cardiovascular disease, 2.10-fold risk of ischemic stroke, 6.02-fold risk of hemorrhagic stroke, and 3.13-fold risk of mortality compared with the control group (all P < 0.0001) after adjusting the confounding factors. In addition, the trend of cumulated incidence risk among MACCE, cardiovascular disease, ischemic and hemorrhagic stroke, and mortality presented the greatest incidence within the first year after diagnosis and persisted during the 5 years of follow-up., Conclusions: Our results showed that patients with TBI have a significantly greater risk of MACCE than the control group. We hope this information will remind critical-care physicians and neurosurgeons to keep in mind the long-term effects of TBI on MACCE., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Traumatic brain injury (TBI) has been reported as a risk factor for the development of brain tumors. However, whether TBI affects systemic cancer remains to be determined. We investigated the incidence and factors associated with cancer development in patients with TBI., Methods: A propensity score (age, gender, and comorbidity)-matched longitudinal cohort study of 34,556 patients with pre-existing TBI and 69,112 patients without TBI from January 2000 to December 2015 was presented using the Taiwan's National Health Insurance Research Database. The Cox proportional hazard regression model was used to estimate the hazard ratio of developing cancer adjusted by the potential confounding factors. The stratified analysis of age, gender, and comorbidities for each cancer type was evaluated using forest plot analysis., Results: The cancer incidence rate in the patients with TBI (4.38%) was greater than that in patients without TBI (3.88%). The interval to cancer development in those with TBI (5.65 ± 3.58 years) was shorter than that in those without TBI (6.02 ± 3.65 years). The cancer risk in those with TBI was increased 1.27-fold compared with that in the general population. Of the patients with TBI, age <55 years and male gender indicated a greater incidence of cancer than that of the general population. The patients with TBI had greater cancer frequencies in the head and neck structures compared with those in the general population., Conclusions: TBI is a risk factor for cancer development, especially in males and those aged <55 years. We hope this information will remind physicians to consider the long-term effects of TBI on cancer development., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Previous studies have implicated traumatic brain injury (TBI) as a risk factor for Parkinson disease (PD). However, the incidence risk of new-onset TBI among patients with PD is not well established. This study investigated the contribution of PD to new-onset TBI associations., Methods: The study selected 6076 patients with PD and using 1:2 propensity score matching 12,152 general population cohorts in a longitudinal population database in Taiwan. The Cox proportional hazard regression model was used to estimate the hazard ratio of TBI adjusted with the potential confounding factors., Results: The incidence of TBI in patients with PD (2.57%) and compared cohorts (1.81%) was significantly different (P = 0.0007). Patients with PD had a higher risk of TBI (hazard ratio, 1.63; 95% confidence interval, 1.32-2.01) compared with the general population. Patients with PD with TBI incidence had a higher Charlson Comorbidity Index than did the general population with TBI (P < 0.0001). Fall is the major cause of TBI in patients with PD., Conclusions: This study shows that patients with PD have a high risk of TBI, and the major cause of TBI in patients with PD is fall., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To determine the neuroprotective mechanisms of tamoxifen (TMX) during traumatic brain injury (TBI), especially the effects on estrogen receptor-α (ERα) expression, as well as neuroinflammatory associations., Materials and Methods: Anesthetized male Sprague-Dawley rats were divided into 4 groups: sham-operated controls, sham-operated controls given TMX (1 mg/kg/per day) for 3 days, those given a vehicle solution immediately after TBI, and those given TMX (1 mg/kg/per day) for 3 days. The functional outcome was evaluated by assessments of body weight and proprioception. The total ERα expression in the cortex also was investigated by Western blotting, and ERα expression in neurons, microglia, and astroglia were each detected via immunofluorescence staining. Neuronal apoptosis (marker caspase-3), activated microglia (marker OX42), astroglia (marker glial fibrillary acidic protein), and tumor necrosis factor-alpha expression in microglia and astroglia in the cortex were evaluated by immunofluorescence staining methods., Results: Compared with sham-operated controls, the TBI-induced proprioception inhibition was significantly attenuated by TMX therapy on day 3 after TBI. Using immunofluorescence staining, we found that the TBI-induced neuronal loss, apoptosis, activated microglia, and astrocyte expression and tumor necrosis factor-alpha and ERα in the cortex were significantly reduced by TMX therapy., Conclusions: Our results suggest that the intraperitoneal injection of TMX (1 mg/kg/per day) for 3 days may affect ERα expression in neurons and glia, which is accompanied by neuroinflammation and neuronal apoptosis, and it might represent one mechanism by which functional recovery occurs. We consider TMX administration to be a promising strategy for TBI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The main aim of this study is to elucidate whether the neuroprotective effect of memantine, a noncompetitive N-methyl-d-aspartate receptor 2B (NR2B) antagonist, affects neuronal nitrosative stress, apoptosis, and NR2B expression and improves functional outcomes., Methods: Immediately after the onset of fluid percussion traumatic brain injury (TBI), anesthetized male Sprague-Dawley rats were divided into sham-operated, TBI + vehicle, and TBI + memantine groups. TBI rats were treated with a memantine intraperitoneal injection dose of 20 mg/kg intraperitoneally and then 1 mg/kg every 12 hours intraperitoneally for 6 doses. The motor function, proprioception, infarction volume, and neuronal apoptosis were then measured. Immunofluorescence was used to evaluate astrogliosis, microgliosis, nitrosative stress, and NR2A and NR2B expression in cortical cells. All the parameters were assessed 72 hours after TBI., Results: Compared with the sham-operated controls, the TBI-induced motor and proprioception deficits, and increased infraction volume after TBI were significantly attenuated by memantine therapy. The TBI-induced neuronal apoptosis, astrogliosis, and microgliosis, the numbers of neuronal NO synthase and 3-nitro-l-tyrosine expression in neurons, and inducible NO synthase expression in microglia and astrocyte cells in the ischemic cortex after TBI were significantly improved by memantine therapy. Simultaneously, without affecting the NR2A expression in neuronal cells, the NR2B expression significantly decreased after memantine therapy, as evaluated by an immunofluorescence stain., Conclusions: Intraperitoneal injection of memantine in the acute stage may ameliorate TBI in rats by affecting NR2B expression and decreasing neuronal apoptosis and nitrosative stress in the injured cortex. These effects might represent 1 mechanism by which functional recovery occurred., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Insomnia, a common symptom after traumatic brain injury (TBI), may be a pre-symptom for developing stroke. This study aims to investigate whether insomnia is a potential risk factor for stroke after TBI, especially early insomnia., Methods: Taiwan's Longitudinal Health Insurance Database 2000 from 1999 to 2013 was used in this cohort study. TBI patients with insomnia were selected based on the ICD-9-CM code (TBI: 801-804 and 850-854; insomnia: 307.4, 327, and 780.5). The outcome we were interested in was stroke (ICD-9-CM: 430-438). The incidence rate ratio of stroke between TBI with insomnia and the general population with insomnia was calculated by Poisson regression. The relative risk adjusted for potential confounding variables was estimated by Cox regression., Results: For 1174 TBI patients with insomnia and 5870 general patients with insomnia, TBI patients have 209.85 incidence risk of new-onset stroke if they have insomnia. TBI patients have 2.28-fold (95% CI: 1.70-3.06) risk of new-onset stroke compared with the general population, even when controlling for age, gender, socioeconomic status, and comorbidities. The hazard ratio of new-onset stroke among different phases of new-onset insomnia after TBI surgery is 1.95-fold (95% CI: 1.05-3.62), 2.75-fold (95% CI: 1.73-4.37), and 2.66-fold (95% CI: 1.68-4.21) at ≤3, 3-12, and 12-24 months, compared with the general population with insomnia, respectively., Conclusion: TBI patients with insomnia have a higher risk of stroke compared with the general population with insomnia. Early new-onset insomnias after TBI will have higher risk of stroke. Therefore, we consider that insomnia could be a signal of the development of new-onset stroke in TBI patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: The aim of this study was to determine whether hyperbaric oxygen (HBO) therapy causes attenuation of traumatic brain injury (TBI)-induced depression-like behavior and its associated anti-neuroinflammatory effects after fluid percussion injury., Methods: Anesthetized male Sprague-Dawley rats were divided into 3 groups: sham operation plus normobaric air (NBA) (21% oxygen at 1 absolute atmosphere [ATA]), TBI plus NBA, and TBI plus HBO (100% oxygen at 2.0 ATA). HBO was applied immediately for 60 min/d after TBI for 3 days. Depression-like behavior was tested by a forced swimming test, motor function was tested by an inclined plane test, and infarction volume was tested by triphenyltetrazolium chloride (TTC) staining on days 4, 8, and 15. Neuronal apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling assay), microglial (marker OX42) activation, and tumor necrosis factor (TNF)-α expression in microglia in the hippocampus CA3 were measured by immunofluorescence methods., Results: Compared with the TBI controls, without significant changes in TTC staining or in the motor function test, TBI-induced depression-like behavior was significantly attenuated by HBO therapy by day 15 after TBI. Simultaneously, TBI-induced neuronal apoptosis, microglial (marker OX42) activation, and TNF-α expression in the microglia in the hippocampus CA3 were significantly reduced by HBO., Conclusions: Our results suggest that HBO treatment may ameliorate TBI-induced depression-like behavior in rats by attenuating neuroinflammation, representing one possible mechanism by which depression-like behavior recovery might occur. We also recommend HBO as a potential treatment for TBI-induced depression-like behavior if early intervention is possible., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The antidepressant-like effects of simvastatin on traumatic brain injury (TBI) remain unclear. The present study aimed to investigate the neuroprotective effects of simvastatin and determine whether simvastatin attenuates TBI-induced depression-like behavior and, more specifically, acts as an antineuroinflammatory., Methods: Anesthetized male Sprague-Dawley rats were divided into five groups: sham-operated controls, TBI controls, and TBI treatment with simvastatin 4, 10, or 20 mg/kg. Simvastatin was intraperitoneally injected 0, 24, and 48 h after TBI. The motor function was measured using an inclined plane, and depression-like behavior was evaluated using forced swimming tests. Neuronal apoptosis (markers: NeuN, TUNEL, caspase-3), microglia (marker: OX42) and astrocyte (marker: GFAP) activation, and TNF-α expression in the microglia and astrocytes of the hippocampal CA3 area were investigated using immunofluorescence assay. All parameters were measured on the 4th, 8th, and 15th day, or only on the 15th day after TBI., Results: TBI-induced depression-like behavior, which increased duration of immobility, was significantly attenuated by 20 mg simvastatin therapy on day 15 after TBI. TBI-induced neuronal apoptosis, microglia and astrocyte activation, and TNF-α expression in the microglia and astrocytes of the CA3 area of the hippocampus were significantly reduced by simvastatin treatment, particularly when 20 mg/kg was administered for 3 days., Conclusions: Intraperitoneal injection of simvastatin attenuated TBI in rats during the acute stage by reducing neuronal apoptosis, microglia, and TNF-α expression, thereby resulting in a reduction of depressive-like behavior. Our results suggest that simvastatin may be a promising treatment for TBI-induced depression-like behavior.

Background: Neuroinflammation is the leading cause of neurological sequelae after traumatic brain injury (TBI). The aim of the present study was to investigate whether the neuroprotective effects of electroacupuncture (EA) are mediated by anti-neuroinflammatory effects in a rat model of TBI., Methods: Male Sprague-Dawley rats were randomly divided into three groups: sham-operated, TBI control, and EA-treated. The animals in the sham-operated group underwent a sham operation, those in the TBI control group were subjected to TBI, but not EA, and those in the EA group were treated with EA for 60 min immediately after TBI, daily for 3 consecutive days. EA was applied at the acupuncture points GV20, GV26, LI4, and KI1, using a dense-dispersed wave, at frequencies of 0.2 and 1 Hz, and an amplitude of 1 mA. Cell infarction volume (TTC stain), neuronal apoptosis (markers: TUNEL and Caspase-3), activation of microglia (marker: Iba1) and astrocytes (marker: GFAP), and tumor necrosis factor (TNF)-α expression in the microglia and astrocytes were evaluated by immunofluorescence. Functional outcomes were assessed using the inclined plane test. All tests were performed 72 h after TBI., Results: We found that TBI-induced loss of grasp strength, infarction volume, neuronal apoptosis, microglial and astrocyte activation, and TNF-α expression in activated microglia and astrocytes were significantly attenuated by EA treatment., Conclusions: Treatment of TBI in the acute stage with EA for 60 min daily for 3 days could ameliorate neuroinflammation. This may thus represent a mechanism by which functional recovery can occur after TBI.

Objective: Depression is a common complication after traumatic brain injury (TBI). This study aimed to evaluate the risk of hyperlipidemia for new-onset depression after TBI and the role of statin medications using a longitudinal population database., Method: A matched longitudinal cohort study of 3,792 subjects (1,264 TBI patients [ICD-9-CM code: 801-804 and 850-854] with preexisting hyperlipidemia [ICD-9-CM code: 272.0, 272.1, 272.2, 272.4] and 2,528 age- and sex-matched TBI patients without hyperlipidemia) was conducted using the Taiwan Longitudinal Health Insurance Database from January 2001 to December 2008. The incidence and hazard ratios (HRs) for the development of new-onset depression (ICD-9-CM code: 296.2X-296.3X, 300.4, and 311.X) after TBI were compared between the 2 groups., Results: The incidence rate of depression in TBI with preexisting hyperlipidemia was 136.61 per 10,000 person-years. TBI patients with preexisting hyperlipidemia had a 1.72-fold increased incidence rate ratio compared with those without hyperlipidemia (P = .0056). A Cox model showed hyperlipidemia to be an independent predictor of depression (HR = 1.61; 95% CI, 1.03-2.53). TBI patients with hyperlipidemia who were not treated with statins experienced a 1.95-fold incidence risk ratio (P = .0017) and higher risk of new-onset depression (HR = 1.61; 95% CI, 1.03-2.53) compared to TBI patients without hyperlipidemia., Conclusions: Preexisting hyperlipidemia could be an independent predictor of new-onset depression in TBI patients, and TBI patients with preexisting hyperlipidemia who were not treated with statins presented a higher risk of new-onset depression than TBI patients without hyperlipidemia. Our findings may provide some insight into the important role of statin medications in the development of new-onset depression in patients with traumatic brain injury., (© Copyright 2016 Physicians Postgraduate Press, Inc.)