Surgically Induced Brain Injury Research Articles

Attenuation of surgically-induced brain injury through whole and fractionated venom protein preconditioning

Attenuation of surgically-induced brain injury through whole and fractionated venom protein preconditioning

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model.

Neurosurgical procedures result in surgically induced brain injury (SBI) that causes postoperative complications including brain edema and neuronal apoptosis in the surrounding brain tissue. SBI leads to the release of cytokines that indirectly cause the stimulation of kynurenine 3-monooxygenase (KMO) and the release of neurotoxic quinolinic acid (QUIN). This study tested a KMO inhibitor, RO 61-8048, to prevent postoperative brain edema and consequent neuronal apoptosis in an in vivo model of SBI. A rodent model of SBI was utilized which involves partial resection of the right frontal lobe. A total of 127 Sprague-Dawley male rats (weight 275-325g) were randomly divided into the following groups: Sham surgical group, SBI, SBI+DMSO, SBI+RO 61-8048 (10mg/kg), SBI+RO 61-8048 (40mg/kg), and SBI+RO 61-8048 (40mg/kg)+KAT II inhibitor PF-04859989 (5mg/kg). RO 61-8048 was administered by intraperitoneal injection after SBI. Postoperative assessment at different time points included brain water content (brain edema), neurological scoring, and western blot. SBI increased brain water content (ipsilateral frontal lobe), decreased neurological function, and increased apoptotic markers compared with sham animals. Treatment with RO 61-8048 (40mg/kg) reduced brain water content and improved long-term neurological function after SBI. RO 61-8048 increased the expression of kynurenic acid while reducing QUIN and apoptotic markers in the surrounding brain tissue after SBI. These neuroprotective effects were reversed by PF-04859989. This study suggests KMO inhibition via RO 61-8048 as a potential postoperative therapy following neurosurgical procedures.

Valproic Acid Pretreatment Reduces Brain Edema in a Rat Model of Surgical Brain Injury.

Surgically induced brain injury (SBI) results in brain edema and neurological decline. Valproic acid (VA) has been shown to be neuroprotective in several experimental brain diseases. In this study, we investigated the pretreatment effect of VA in a rat model of SBI. A total of 57 male Sprague-Dawley rats were use in four groups: sham, SBI + vehicle, SBI + low dose (100 mg/kg) VA, and SBI + high dose (300 mg/kg) VA. SBI was induced by partially resecting right frontal lobes. Shams underwent identical surgical procedures without brain resection. VA or vehicle was administered subcutaneously 30 min prior to SBI. At 24 and 72 h post SBI, neurobehavior and brain water content were assessed as well as matrix metalloproteinases (MMPs) activities. There was significantly higher brain water content within the right frontal lobe in SBI rats than in shams. Without neurobehavioral improvements, the low-dose but not high-dose VA significantly reduced brain edema at 24 h post SBI. The protection tends to persist to 72 h post SBI. At 24 h post SBI, low-dose VA did not significantly reduce the elevated MMP-9 activity associated with SBI. In conclusion, VA pretreatment attenuated brain edema at 24 h after SBI but lacked MMP inhibition. The single dose VA was not associated with neurobehavioral benefits.

Epsilon Aminocaproic Acid Pretreatment Provides Neuroprotection Following Surgically Induced Brain Injury in a Rat Model.

Neurosurgical procedures can damage viable brain tissue unintentionally by a wide range of mechanisms. This surgically induced brain injury (SBI) can be a result of direct incision, electrocauterization, or tissue retraction. Plasmin, a serine protease that dissolves fibrin blood clots, has been shown to enhance cerebral edema and hemorrhage accumulation in the brain through disruption of the blood brain barrier. Epsilon aminocaproic acid (EAA), a recognized antifibrinolytic lysine analogue, can reduce the levels of active plasmin and, in doing so, potentially can preserve the neurovascular unit of the brain. We investigated the role of EAA as a pretreatment neuroprotective modality in a SBI rat model, hypothesizing that EAA therapy would protect brain tissue integrity, translating into preserved neurobehavioral function. Male Sprague-Dawley rats were randomly assigned to one of four groups: sham (n = 7), SBI (n = 7), SBI with low-dose EAA, 150 mg/kg (n = 7), and SBI with high-dose EAA, 450 mg/kg (n = 7). SBI was induced by partial right frontal lobe resection through a frontal craniotomy. Postoperative assessment at 24 h included neurobehavioral testing and measurement of brain water content. Results at 24 h showed both low- and high-dose EAA reduced brain water content and improved neurobehavioral function compared with the SBI groups. This suggests that EAA may be a useful pretherapeutic modality for SBI. Further studies are needed to clarify optimal therapeutic dosing and to identify mechanisms of neuroprotection in rat SBI models.

Propofol Pretreatment Fails to Provide Neuroprotection Following a Surgically Induced Brain Injury Rat Model.

Neurosurgical procedures are associated with unintentional damage to the brain during surgery, known as surgically induced brain injuries (SBI), which have been implicated in orchestrating structural and neurobehavioral deterioration. Propofol, an established hypnotic anesthetic agent, has been shown to ameliorate neuronal injury when given after injury in a number of experimental brain studies. We tested the hypothesis that propofol pretreatment confers neuroprotection against SBI and will reduce cerebral edema formation and neurobehavioral deficits in our rat population. Sprague-Dawley rats were treated with low- and high-dose propofol 30 min before SBI. At 24 h post injury, brain water content and neurobehavioral assessment was conducted based on previously established models. In vehicle-treated rats, SBI resulted in significant cerebral edema and higher neurological deficit scores compared with sham-operated rats. Low- or high-dose propofol therapy neither reduced cerebral edema nor improved neurologic function. The results suggest that propofol pretreatment fails to provide neuroprotection in SBI rats. However, it is possible that a SBI model with less magnitude of injury or that propofol re-dosing, given the short-acting pharmacokinetic property of propofol, may be needed to provide definitive conclusions.

PAR-1 antagonist SCH79797 ameliorates apoptosis following surgical brain injury through inhibition of ASK1-JNK in rats

Neurosurgical procedures inevitably produce intraoperative hemorrhage. The subsequent entry of blood into the brain parenchyma results in the release of large amounts of thrombin, a known contributor to perihematomal edema formation and apoptosis after brain injury. The present study seeks to test 1) the effect of surgically induced brain injury (SBI) on thrombin activity, expression of thrombin's receptor PAR-1, and PAR-1 mediated apoptosis; 2) the effect of thrombin inhibition by argatroban and PAR-1 inhibition by SCH79797 on the development of secondary brain injury in the SBI model on rats.A total of 88 Sprague–Dawley male rats were randomly divided into sham, vehicle-, argatroban-, or SCH79797-treated groups. SBI involved partial resection of the right frontal lobe under inhalation isoflurane anesthesia. Sham-operated animals received only craniotomy. Thrombin activity, brain water content, and neurological deficits were measured at 24h following SBI. Involvement of the Ask1/JNK pathway in PAR-1-induced post-SBI apoptosis was characterized by using Ask1 or JNK inhibitors.We observed that SBI increased thrombin activity, yet failed to demonstrate any effect on PAR-1 expression. Argatroban and SCH79797 reduced SBI-induced brain edema and neurological deficits in a dose-dependent manner. SBI-induced apoptosis seemed mediated by the PAR-1/Ask1/JNK pathways. Administration of SCH79797 ameliorated the apoptosis following SBI.Our findings indicate that PAR-1 antagonist protects against secondary brain injury after SBI by decreasing both brain edema and apoptosis by inactivating PAR-1/Ask1/JNK pathway. The anti-apoptotic effect of PAR-1 antagonists may provide a promising path for therapy following SBI.

Potential application of hydrogen in traumatic and surgical brain injury, stroke and neonatal hypoxia-ischemia

This article summarized findings of current preclinical studies that implemented hydrogen administration, either in the gas or liquid form, as treatment application for neurological disorders including traumatic brain injury (TBI), surgically induced brain injury (SBI), stroke, and neonatal hypoxic-ischemic brain insult (HI). Most reviewed studies demonstrated neuroprotective effects of hydrogen administration. Even though anti-oxidative potentials have been reported in several studies, further neuroprotective mechanisms of hydrogen therapy remain to be elucidated. Hydrogen may serve as an adjunct treatment for neurological disorders.

MATRIX METALLOPROTEINASE INHIBITION ATTENUATES BRAIN EDEMA IN AN IN VIVO MODEL OF SURGICALLY-INDUCED BRAIN INJURY

Neurosurgical procedures can result in brain injury by various means, including direct trauma, hemorrhage, retractor stretch, and electrocautery. This surgically-induced brain injury (SBI) can cause postoperative complications such as brain edema after blood-brain barrier (BBB) disruption. The present study seeks to test a matrix metalloproteinase (MMP) inhibitor for preventing postoperative brain edema and BBB disruption in an in vivo model of surgically-induced brain injury. A rodent model of SBI was used which involves resection of a part of the right frontal lobe. A total of 89 Sprague-Dawley male rats (weight, 300-350 g) were randomly divided into four groups: 1) SBI with vehicle treatment (0.1% dimethyl sulfoxide), 2) SBI with single treatment of MMP inhibitor-1 (an inhibitor of MMP-9 and MMP-2), 3) SBI treated daily (total 3 times) with MMP inhibitor-1, and 4) sham surgical group. Postoperative assessment at different time periods included evaluation of BBB permeability, brain water content (brain edema), neurological scoring, histology, immunohistochemistry, and zymography for MMP enzymatic activity. Temporal magnetic resonance imaging studies were also performed to assess postoperative edema. The results indicate that SBI caused increased brain water content (ipsilateral frontal lobe) and BBB permeability compared with sham animals. Treatment with MMP inhibitor-1 attenuated MMP-9 and MMP-2 activity and decreased brain water content with preservation of the BBB. Inhibition of MMP-9 and MMP-2 attenuates brain edema and BBB disruption after SBI. The study suggests a potential role for MMP inhibition as preoperative therapy before neurosurgical procedures.

NADPH oxidase inhibition improves neurological outcomes in surgically-induced brain injury

Neurosurgical procedures can result in brain injury by various means including direct trauma, hemorrhage, retractor stretch, and electrocautery. This surgically-induced brain injury (SBI) can cause post-operative complications such as brain edema. By creating a mouse model of SBI, we tested whether NADPH oxidase, an important reactive oxygen species producing enzyme, is involved in SBI using transgenic mice lacking gp91 phox subunit of NADPH oxidase (gp91 phox KO) and apocynin, a specific inhibitor of NADPH oxidase. Neurological function and brain edema were evaluated at 24 h post-SBI in gp91 phox KO and wild-type littermates grouped into SBI and sham-surgery groups. Alternatively, mice were grouped into vehicle- and apocynin-treated (5 mg/kg, i.p. 30 min before SBI) groups. Oxidative stress indicated by lipid peroxidation (LPO) was measured at 3 and 24 h post-SBI. The gp91 phox KO mice, but not the apocynin-treated mice showed significantly improved neurological scores. Brain edema was observed in both gp91 phox KO and wild-type groups after SBI; however, there was no significant difference between these two groups. Brain edema was also not affected by apocynin-pretreatment. LPO levels were significantly higher in SBI group in both gp91 phox KO and wild-type groups as compared to sham group. A trend, although without statistical significance, was noted towards attenuation of LPO in the gp91 phox KO animals as compared to wild-type group. LPO levels were significantly attenuated at 3 h post-SBI by apocynin-pretreatment but not at 24 h post-SBI. These results suggest that chronic and acute inhibition of NADPH oxidase activity does not reduce brain edema after SBI. Long-term inhibition of NADPH oxidase, however improves neurological functions after SBI.

NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE INHIBITION IMPROVES NEUROLOGIC FUNCTIONS IN SURGICALLY INDUCED BRAIN INJURY.

Purpose Neurosurgical procedures can result in brain injury by various means, including direct trauma, hemorrhage, retractor stretch, and electrocautery. This surgically induced brain injury (SBI) can cause postoperative complications such as brain edema following blood-brain barrier (BBB) disruption. In this study, we tested whether NADPH oxidase, an important reactive oxygen species (ROS)-producing enzyme, is involved in SBI using transgenic mice lacking gp91phox subunit of NADPH oxidase (gp91-KO) and apocynin, a specific inhibitor of NADPH oxidase. Methods A mouse model of surgically induced brain injury (SBI) was used, which involves stereotaxic resection of a part of the right frontal lobe. gp91-KO and wild-type (WT, C57BL/6J) littermates were grouped into SBI and sham-surgery groups. Alternatively, mice were grouped into SBI and apocynin-treated (5 mg/kg, IP 30 minutess before surgery) groups. Neurologic function and brain edema (brain water content) were evaluated at 24-hour post-SBI. Oxidative stress indicated by lipid peroxidation (LPO) was measured at 3 and 24 hours post-SBI. Results Brain edema was observed 24-hour post-SBI in both gp91-KO and wild-type group as compared with the sham group; however, there was no significant difference between the gp91-KO and wild-type groups. Brain edema was also not affected by apocynin pretreatment. LPO levels were significantly higher in SBI group in both gp91-KO and wild-type groups compared with the sham group. LPO levels were significantly attenuated at 3-hour post-SBI by apocynin pretreatment but not at 24-hour post-SBI. A trend, although without statistical significance, was noted toward attenuation of LPO in the gp91-KO animals as comp. The gp91-KO mice and apocynin-treated mice, however, showed significantly improved neurologic scores 24-hour post-SBI compared with the wild-type and vehicle-treated mice, respectively. Conclusions Chronic and acute inhibition of NADPH oxidase activity does not affect brain edema; however, it improves neurologic functions after SBI. Further investigation is needed to find if other mechanisms, such as apoptosis or inflammation, are involved in improved neurologic functions after NADPH oxidase inhibition.

Surgically induced brain injury in rats: The effect of erythropoietin

Brain tissue at the edge of a surgical resection site is at risk for damage from direct trauma, retractor stretch, hemorrhage, edema, and electrocautery. In this study we used a new rodent model of surgically induced brain injury (SBI) to study this tissue at the edge of a resection site. The SBI model entails stereotaxic resection of part of the right frontal lobe. We tested pretreatment with erythropoietin, a known neuroprotectant, for protective effects in this model. Three groups of male Sprague–Dawley rats (280–330g) were used: SBI without treatment (n=63), SBI with EPO treatment (n=76), and Sham surgery (n=12). Rats were sacrificed 24h, 72h, and 7 days after SBI or Sham surgery. Postoperative assessment included mortality, histology, immunohistochemistry, Evans blue exudation, brain water content, and magnetic resonance imaging. No difference was found between untreated and EPO-treated groups in mortality, histology, TUNEL, magnetic resonance imaging, or blood–brain-barrier breakdown. The EPO-treated group had statistically more brain water content at 24h than the untreated group. Immunohistochemistry demonstrated a qualitative increase in VEGF in the EPO-treatment group. We conclude that EPO does not ameliorate damage in SBI, and may increase brain edema early after surgery.