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Research article

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Neuroprotective effects of MK-801 against traumatic brain injury in immature rats.

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Atac¸ Sönmez a,∗ , Oya Saym b , Seren Güls¸en Gürgen c , Meryem C¸alis¸ir d a

Department of Physiology, Faculty of Medicine, Dokuz Eylül University, 35340 Balcova Izmir, Turkey Research Laboratory, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey Department of Histology and Embriyology, Medical Faculty, Celal Bayar University, Manisa, Turkey d Health Science Institute, Laboratory Animal Science, Dokuz Eylül University, Izmir, Turkey b c

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h i g h l i g h t s • • • •

Traumatic brain injury induced neuronal cell death in hippocampus. Traumatic brain injury decreased expression of BDNF, NGF and NMDR in hippocampus. Trauma increased anxiety and impaired hippocampal dependent memory in immature rats. MK-801 ameliorated histopathological, and behavioral consequences of trauma.

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Article history: Received 11 March 2015 Received in revised form 15 April 2015 Accepted 1 May 2015 Available online xxx

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Keywords: Immature rats Traumatic brain injury MK-801 Hippocampus BDNF NGF NMDAR Cognition

Traumatic brain injury (TBI) is a major health problem in pediatric ages and also has major social, economic, and emotional outcomes, with diverse sequelae in many spheres of everyday life. We aimed to investigate the effect of MK-801, a competitive NMDA receptor antagonist, on hippocampal damage and behavioral deficits on 10-day-old rat pups subjected to contusion injury. The aims of the present Q3 study were to determine: (i) the short term effects of MK-801 on hippocampal BDNF, NGF and NMDA receptor immunoreactivity and neuron density in hippocampus (ii) long term effects of MK-801 on cognitive dysfunction following TBI in the immature rats. MK-801, was injected intraperitoneally at the doses of 1 mg/kg of body weight immediately after induction of traumatic injury. Hippocampal damage was examined by cresyl violet staining, BDNF, NGF and NMDAR receptor immunohistochemistry on P10 day and behavioral alterations were evaluated using elevated plus maze and novel object recognition tests two months after the trauma. Histopathological and immunohistochemical evaluations showed that treatment with a single dose of 1 mg/kg MK-801 (i.p.) significantly ameliorated the trauma induced hippocampal neuron loss and decreased BDNF, NGF and NMDAR expressions in CA1, CA3 and DG hippocampal brain regions. Additionally, treatment with MK-801 ameliorated anxiety and hippocampus dependent memory of animals subjected to trauma. These results show that acute treatment of MK-801 has a neuroprotective role against trauma induced hippocampal neuron loss and associated cognitive impairment in immature rats. © 2015 Published by Elsevier Ireland Ltd.

1. Introduction

Abbreviations: TBI, traumatic brain injury; EAA, excitatory amino acid; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; EPM, elevated plus maze; NORT, novel object recognition test; DI, discrimination index. Q2 ∗ Corresponding author. Tel.: +90 533 342 70 08; fax: +90 533 342 70 08. E-mail addresses: [email protected], [email protected] (A. Sönmez).

Although traumatic brain injury (TBI) is a leading cause of injury death and disability, and persons of all ages, races/ethnicities, and incomes are affected, the highest combined rates of TBI-related Emergency Department visits, hospitalizations, and deaths occur in young children [1]. Long-term TBI-related disability results in reduced quality of life for the patient and prolonged medical, social, and economic effects on society. Although children have better survival rates as compared to adults with head trauma, the long-term sequel and consequences are often more devastating

http://dx.doi.org/10.1016/j.neulet.2015.05.001 0304-3940/© 2015 Published by Elsevier Ireland Ltd.

Please cite this article in press as: A. Sönmez, et al., Neuroprotective effects of MK-801 against traumatic brain injury in immature rats. Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.05.001

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Table 1 Quantitative histopathological analysis of hippocampal CA1, CA3, and DG regions of rats 4 days after the trauma.

CA1 CA3 DG * ** ***

Control

Trauma

MK-801

57 ± 1.1* 41 ± 0.7* 64 ± 1.0*

49 ± 0.9** 34 ± 0.8** 53 ± 0.8**

55 ± 0.8*** 40 ± 0.9*** 60 ± 1.0***

p < 0.001 compared with the trauma group. p < 0.01 compared with the MK-801 group. p < 0.05 compared with the control group.

in children due to their age and developmental potential. Moreover, Barlow et al. reported that extended follow-up of preschool 46 children after severe TBI revealed learning difficulties, attention 47 deficits and memory problems that did not become manifest until 48 49Q4 the children entered school [2]. Brain damage from TBI can be divided into the primary and the 50 secondary. Soon after the trauma, primary injury occurs as a result 51 of mechanical damage of brain tissue by direct or indirect impact to 52 brain and cannot be avoided [16,28]. The primary injury can be less53 ened through preventive measures, such as education of potential 54 victims, use of safety equipments and enforcing laws for individual 55 and public safety [1]. 56 Secondary brain injury, which is triggered by primary brain 57 injury, occurs several hours or even days later after the trauma 58 and significantly contributes to the prognosis of patients suffering 59 from TBI. Excitotoxicity, apoptosis, intracellular Ca2+ overloading, 60 inflammatory mediators, overoxidation of oxygen free radical and 61 lipid peroxidase are major pathophysiologic mechanisms causing 62 secondary brain injury. Unfortunately, no effective treatments to 63 abate secondary injuries are currently available. Treatment with 64 competitive NMDA receptor antagonists, such as MK-801 has been 65 suggested as an effective mechanism to reduce excitatory amino 66 acid (EAA) release following TBI [3–6]. 67 Two major neurotrophic factors, nerve growth factor (NGF) and 68 brain-derived neurotrophic factor (BDNF) are involved in several 69 physiological processes associated with neuronal growth, sur70 vival and plasticity. Increasing number of papers demonstrating 71 their ability to serve as neuroprotective molecules under various 72 pathological conditions [7,8]. However neuroprotective effects of 73 neurotrophic factors after TBI is still controversial. Additionally, 74 there is no information about their expression in hippocampal brain 75 regions in immature rats and effects of MK-801 on their expression 76 after the trauma. 77 The aims of the present study were to determine: (i) the short 78 term effects of MK-801 on hippocampal BDNF, NGF and NMDA 79 receptor immunoreactivity and neuron density in hippocampus (ii) 80 long term effects of MK-801 on cognitive dysfunction following TBI 81 in the immature rats. 82 and Table 1 83 45

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2. Material and methods All experiments were performed in accordance with the guidelines provided and approved by the Animal Care and Use Committee of the Dokuz Eylül University, School of Medicine. Forty-two litters (Wistar Albino rats) were randomly allocated into three groups at 10 days of postnatal age (P10): a control group, a trauma group, and a MK-801 treatment group, each having fourteen rats. Control group received no medication, trauma group received physiological saline as a vehicle control for MK-801 group and MK801 group received a single dose of 1 mg/kg MK-801 (i.p.) (Sigma, USA) immediately after trauma. We used a modification of a well-described percussion trauma model in immature rats on P10, in an attempt to model infant and early childhood head trauma as we described previously [9]. All the

pups were kept on a heating pad until returned to their mothers at 4 h after the trauma. Four days after trauma, seven animals from each groups were randomly separated for histological evaluations, brain tissues were collected after cervical dislocation and fixed in 10% formalin solution for 24 h. Collected tissues were embedded in paraffin blocks after processing using routine protocols. 5 ␮m sections were taken using microtome. Sections were divided into two samples to be used for histochemical and immunohistochemical assays. For histochemical analysis all sections were stained with Hematoxylin-eosin using routine protocol. Each sample was subjected to the estimation of neuron number by taking three coronal sections through the hippocampus corresponding approximately to Plates 21, 23, 25 in the rat atlas of Paxinos and Watson [10]. The images were analyzed by using a computer assisted image analyzer system consisting of a microscope and a video camera. The images were grabbed with the video camera at 3.3× magnification; the hemispheric areas were viewed on the monitor and outlined by drawing. The numbers of neurons in hippocampal dentate gyrus, CA1 and CA3 regions of both hemispheres were counted by a 15,000-␮m2 counting frame viewed through a 40× lens at the monitor. The counting frame was placed randomly five times on the image analyzer system monitor and the numbers of neurons were counted (Q Win V3 Plus Image) and the average was taken. All counting and measurement procedures were performed blindly. For immunohistochemical analysis, sections were deparaffinized at 60 ◦ C overnight and xylene for 30 min. Sections were first rehydrated in a series of baths with decreasing amounts of ethanol. After washing with distilled water and then phosphatebuffered saline (PBS) for 10 min each, they were incubated with 2% tyripsin at 37 ◦ C for 15 min. Sections were marked with a Dako pen and were added 3% H2 O2 solution for 15 min to inhibit endogenous peroxidase activity. The primary antibodies NGF (Abcam, Cambridge, MA), BDNF (Santacruz, CA, USA) and NMDAR (Abcam) were applied in a dilution of 1:100 at 4 ◦ C overnight. After washing with PBS three times, the secondary antibodies biotinylated IgG and streptavidin-peroxidase conjugate (supplied ready to use) were incubated for 30 min. To detect immunolabelling, 50 ␮L of 3-amino-9-ethylcarbazole (Invitrogen, USA) was added to each section and observed after 5 min. They were washed with distilled water and counterstained with Mayer’s hematoxylin for 5 min. After washing with distilled water one more time, sections were covered with mounting media. As long as the same treatment was received by the negative control sections, instead of the primary antibodies, they were incubated with rabbit IgG or mouse IgG. All specimens were then evaluated under a light microscope. Two observers blinded to the experimental data evaluated the immunolabeling scores independently of one another. The staining intensity of slides processed using the immunohistochemical protocol was graded semi-quantitatively, and the HSCORE was calculated using the equation HSCORE= Pi (i + 1), where i = the intensity of staining, Q5 with a value of 1, 2 or 3 (weak, moderate or strong, respectively), and Pi is the percentage of stained cells for each intensity, varying from 0 to 100% [11]. Elevated Plus Maze (EPM) test assessed anxiety-like behavior in the animals on P60 [12,13]. The maze was made of two identical open arms and two identical closed arms to form a “+” shape. The apparatus was elevated 50 cm above the floor. The rats were situated at the middle of the maze facing one of the open parts. Then the rats were enabled to explore the maze for 3 min. The time the rats spent at the open arms was measured and analyzed using EthoVisionXT video tracking software. The longer the rats were at the open arms they were considered to manifest a lesser anxiety-like behavior. Results are expressed as mean ± SE of the percentage of time spent in the open arm of the maze.

Please cite this article in press as: A. Sönmez, et al., Neuroprotective effects of MK-801 against traumatic brain injury in immature rats. Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.05.001

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Fig. 1. Hematoxylin-eosin staining in region of hippocampus. Control (A), trauma (B), trauma + MK-801 (C). DG: dentate gyrus, CA1: cornu ammonis area1, CA3: cornu ammonis area3, GCL: granule cell layer, SP: stratum pyramidale. DG region (1), CA3 region (2), CA1 region (3). (A–C) Bar = 100 ␮m, (1–3) Bar = 10 ␮m. Table 2 Quantitative analysis of BDNF, NGF, and NMDR immunoreactivities in hippocampal CA1, CA3, and DG regions of experiment animals, 4 days after the TBI.

BDNF

NGF

NMDAR

* **

Regions

Control

CA1 CA3 DG CA1 CA3 DG CA1 CA3 DG

285 296 264 239 252 230 183 193 177

± ± ± ± ± ± ± ± ±

1.97 3.02 3.1 3.3 3 5.3 2.2 1.8 2.3

Trauma 103 109 98 106 111 98 88 94 86

± ± ± ± ± ± ± ± ±

1.79* 1.22* 1.5* 1.52* 1.3* 1.5* 1.6* 1.5* 1.4*

MK-801 207 216 205 214 222 204 192 199 183

± ± ± ± ± ± ± ± ±

1.86** 2.27** 1.85** 1.75** 2.3** 2.6** 2.27 1.89 1.7

p < 0.001 compared with the control and MK-801 groups. p < 0.01 compared with the control group.

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On P61, the novel object recognition test (NORT) is used to evaluate memory function in rats as described our previous study [9]. Trials were recorded and analyzed using an automated video tracking software. The time measured as an exploration behavior was used to calculate a memory discrimination index (DI):DI = (N−F)/(N+F), where N, is the time spent exploring the new object and F, is the time spent exploring the familiar object. Higher DI is considered to reflect greater memory ability. Data were analyzed using a SPSS 15.0 for Windows program on a computer. Results were expressed as mean ± S.E.M and analyzed by using one-way analysis of variance followed by the Tukey HSD test. A p-value < 0.05 was considered statistically significant.

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To investigate whether treatment with MK-801 protects hippocampal damage after the trauma, we examined the neuron density in hippocampal DG, CA1 and CA3 regions of both hemispheres (Fig. 1). In the trauma group, hippocampal neuron density was significantly decreased in the all regions of hippocampus when compared to control (p < 0.001) and MK-801 (p < 0.01) groups. However, treatment with MK-801 significantly preserved the neurons of all hippocampal regions affected by TBI as compared to traumatized-nontreated rats (p < 0.01). Immunohistochemical analysis used to evaluate the effects of trauma and MK-801 on BDNF, NGF and NMDR expression in hippocampal CA1, CA3, and DG regions, (Figs. 2A,B and 3 and Table 2).

Four days after the trauma BDNF, NGF, and NMDR immunoreactivities significantly decreased in CA1, CA3, and DG regions of hippocampus (p < 0.001). Treatment with MK-801 increased BDNF, NGF, and NMDR immunoreactivity when compared trauma group (p < 0.001). BDNF and NGF, immunoreactivities in hippocampal regions of the MK-801 group was significantly decreased when compared to control group (p < 0.01). The EPM was used in order to examine anxiety levels. Anxiety level of the rats with trauma (21.35% ± 3.4) was significantly reduced when compared to control (32.46% ± 4.6) (p < 0.01), and Q6 MK-801 treated (29.51% ± 4.4) rats (p < 0.05). There was no statistical difference between control and MK-801 treated rats. The effect of MK-801 treatment on posttraumatic memory deficit was examined by applying the NORT. DI performances of the control and MK-801-treated groups (0.61 ± 0.04 and 0.48 ± 0.08, respectively) were significantly higher when compared to the trauma group (0.19 ± 0.06) (p < 0.01 and p < 0.05, respectively), indicating that the MK-801-treatment reversed memory impairment induced by traumatic injury. 4. Discussions The major findings of this study are as follows: (1) traumatic brain injury in immature rats induced neuronal cell death and decreased BDNF, NGF and NMDR immunoreactivity in CA1, CA3, and DG regions of the hippocampus; (2) long-term neurobehavioral effects of trauma increased anxiety and impaired hippocampal dependent memory; (3) administration of MK-801 immediately after the trauma ameliorated histopathological, neurochemical and behavioral consequences of trauma. The processes causing secondary injury results in brain edema, increased intracranial pressure, and impaired cerebral perfusion [28]. This combination of cellular and physiologic disturbances causes increased neuronal cell death, enlargement of infarct size, and neurological, motor, and cognitive impairment. Two brain structures prominently affected in head trauma are the cortex and the hippocampus, which play a crucial role in the processing of spatial memory and learning [27,29]. Our previous [9] and present study showed that hippocampal neuronal loss is not limited to ipsilateral hippocampal areas but it also occurs at contralateral hippocampal areas in immature rat brains. MK-801 administration preserved hippocampal neuronal loss and related memory decline.

Please cite this article in press as: A. Sönmez, et al., Neuroprotective effects of MK-801 against traumatic brain injury in immature rats. Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.05.001

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Fig. 2. (A) NGF immunostaining in region of hippocampus. Control (A), trauma (B), trauma + MK-801 (C). DG: dentate gyrus, CA1: cornu ammonis area1, CA3: cornu ammonis area3, GCL: granule cell layer, SP: stratum pyramidale. DG region (1), CA3 region (2), CA1 region (3). (A–C) Bar = 100 ␮m, (1–3) Bar = 10 ␮m. (B) BDNF immunostaining in region of hippocampus. Control (A), trauma (B), trauma + MK-801 (C). DG: dentate gyrus, CA1: cornu ammonis area1, CA3: cornu ammonis area3, GCL: granule cell layer, SP: stratum pyramidale. DG region (1), CA3 region (2), CA1 region (3). (A–C) Bar = 100 ␮m, (1–3) Bar = 10 ␮m.

Previously reported that mechanical trauma, induced by the weight drop model to the immature rat brain, causes an acute excitotoxic lesion within the area of impact which rapidly expands 231 Q7 within 4 h after trauma [32]. Bittigau et al. also reported that this 232 local excitotoxic response is followed by disseminated apoptotic 233 cell death affecting many brain regions (frontal, parietal, cingulate 234 and retrosplenial cortices, laterodorsal, mediodorsal and ventral 235 thalamic nuclei, hippocampal dentate gyrus, subiculum and stria236 tum) ipsi- and contralateral to the trauma site long after the 237 excitotoxic degeneration which is reached a peak at 24 h follow238 229 230

ing trauma in the brains of pups and subsided at 5 days after the insult [17]. It has been also shown that glutamate excitotoxicity to induce apoptosis in both neuronal and non-neuronal cells via a group of cysteine proteases known as caspases [18]. We conclude that widespread neuronal cell loss affecting the ipsi- and contralateral hippocampal brain areas to the trauma site is due to excitotoxicity and related apopitosis and consistent with previous reports. Glutamate is EAA that is released in high concentrations in extracellular space and cerebrospinal fluid soon after TBI. The regional

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Fig. 3. NMDAR immunostaining in region of hippocampus. Control (A), trauma (B), trauma + MK-801 (C). DG: dentate gyrus, CA1: cornu ammonis area1, CA3: cornu ammonis area3, GCL: granule cell layer, SP: stratum pyramidale. DG region (1), CA3 region (2), CA1 region (3). (A–C) Bar = 100 ␮m, (1–3) Bar = 10 ␮m. 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285

distribution of NMDA and non-NMDA receptors is directly related to excitotoxicity in specific regions of the brain following TBI [14]. Activation of NMDA receptor allows the influx of Na+ and Ca2+ into the cell. As a result, global or extrasynaptic NMDAR stimulation decreases ERK activation, and extrasynaptic NMDAR stimulation decreases CREB activation and BDNF production [15]. Present study showed that NMDR expression four days after the trauma decreased in CA1, CA3 and DG regions of the hippocampus and administration of MK-801, soon after the trauma reversed trauma related reduction of NMDR expression. Different NMDR expression patterns between groups in our study may reflects different neuronal death and survival ratio of each group It was previously shown that although the density of activated NMDRs dramatically increased in the hippocampus and decreased in the cortex 15 min after the trauma, activated NMDRs and NR1, NR2A, and NR2B subunit expressions declined gradually in both hippocampus and cortex in mice [19]. Kumar et al. also demonstrated a decrease in hippocampal NMDAR subunits protein levels which lasted 6–12 h following cortical impact injury [20]. Giza et al. also reported a subunit-specific reduction in synaptic NR2 composition, occur transiently in neocortex and persist at least for 4 days after injury in hippocampus following developmental TBI [26]. Our study showed that expressions of BDNF and NGF in all hippocampal regions decreased four days after the trauma and treatment with MK-801 ameliorated this decline. Cassol Jr. et al. reported that acute low dose of MK-801 prevents memory deficits without altering BDNF levels in sepsis survivor rats [21]. Conte et al. also reported that exogenous BNDF infusion does not affect neuronal survival or behavioral outcome following experimental TBI in mice [22]. We suppose that using external agents such as MK-801 to stimulate expression of neuropeptides such as BDNF and NGF might have better results instead of using exogenous neuropeptides to overcome with secondary brain injury after the TBI. NORT was used to evaluate hippocampal- and cortical dependent nonspatial learning and memory levels. This task requires the capacity to discriminate between previously encountered objects and never-before-encountered objects, which is the operational

definition of object-recognition memory. Hippocampus, which plays a prominent role in cognitive functions, has a high density of glutamate receptors which may make hippocampus more vulnerable to excitotoxic insults after the trauma. Hippocampal dysfunctions, including a suppression of long-term potentiation, and deficiency in learning and memory, have been reported following TBI in rats [23]. Previous studies reported that administration of MK-801 to animal with head trauma injury resulted with better learning and memory scores in different animal studies [24,25]. Our finding showed that traumatic brain injury caused a failure to distinguish between a familiar and a novel object. This finding is consistent with previous reports about trauma induced cognitive impairments in immature brains of both humans and rodent [4,23–25]. Our results showed that treatment with MK-801 has positive effects anxiety-like behaviors seen long time after the trauma in immature rats. Previous studies concluded that anxiety-like behaviors are related hippocampal 5HT receptors which are related with CREB-dependent BDNF expression [30] In conclusion, TBI causes widespread excitotoxic and related apoptotic cell death, decreased BDNF, NGF and NMDR expressions in ipsi and contrlateral hippocampal regions of immature rats, 4 days after the trauma. Long term behavioral effects of TBI in immature rat brain are spatial memory decline and deterioration of anxiety-like behaviors. Glutamate receptor antagonist MK-801 decreases trauma induced hippocampal damage and related neurochemical and behavioral impairments in immature rats. References [1] V.G. Coronado, L. Xu, S.V. Basavaraju, L.C. McGuire, M.M. Wald, M.D. Faul, B.R. Guzman, J.D. Hemphill, Centers for disease control and prevention – surveillance for traumatic brain injury-related deaths United States, 1997–2007, MMWR Surveill. Summ. 60 (5) (2011) 1–32. [2] K.M. Barlow, E. Thomson, D. Johnson, R.A. Minns, Late neurologic and cognitive sequelae of inflicted traumatic brain injury in infancy, Pediatrics 116 (2005) 174–185. [3] S.S. Panter, A.I. Faden, Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury, Neurosci. Lett. 136 (2) (1992) 165–168.

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Please cite this article in press as: A. Sönmez, et al., Neuroprotective effects of MK-801 against traumatic brain injury in immature rats. Neurosci. Lett. (2015), http://dx.doi.org/10.1016/j.neulet.2015.05.001

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Neuroprotective effects of MK-801 against traumatic brain injury in immature rats.

Traumatic brain injury (TBI) is a major health problem in pediatric ages and also has major social, economic, and emotional outcomes, with diverse seq...
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