Atormac
Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 4633  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Search
 
  » Next article
  » Previous article 
  » Table of Contents
  
 Resource Links
  »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
  »  Article in PDF (1,156 KB)
  »  Citation Manager
  »  Access Statistics
  »  Reader Comments
  »  Email Alert *
  »  Add to My List *
* Registration required (free)  

 
  In this Article
 »  Abstract
 »  Introduction
 »  Materials and Me...
 »  Results
 »  Discussion
 »  Conclusion
 »  Acknowledgments
 »  References
 »  Article Figures
 »  Article Tables

 Article Access Statistics
    Viewed3552    
    Printed197    
    Emailed3    
    PDF Downloaded159    
    Comments [Add]    
    Cited by others 10    

Recommend this journal

 


 
ORIGINAL ARTICLE
Year : 2010  |  Volume : 58  |  Issue : 1  |  Page : 29-34

Conditional downregulation of brain- derived neurotrophic factor and tyrosine kinase receptor B blocks epileptogenesis in the human temporal lobe epilepsy hippocampus


Department of Neurology, The First Affiliated Hospital of Harbin Medical University, China

Date of Acceptance13-Aug-2009
Date of Web Publication8-Mar-2010

Correspondence Address:
Liming Zhang
Department of Neurology, The First Affiliated Hospital of Harbin Medical University, No. 23, Youzheng Street, Nangang District, Harbin, Heilongjiang - 150 001
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.60392

Rights and Permissions

 » Abstract 

Background : Brain-derived neurotrophic factor (BDNF) has been implicated as a potential therapeutic target in temporal lobe epilepsy (TLE). However, whether BDNF exerts an epileptogenic or antiepileptogenic function remains controversial. Materials and Methods : BDNF/tyrosine kinase receptor B (trkB) expression levels were comparatively assessed in the hippocampal tissue of TLE patients with (HS group) and without hippocampal sclerosis (non-HS group) as well as from non-epileptic controls. Results : Immunohistochemistry and immunoblot analysis revealed a marked increase in BDNF/trkB expression in the dentate gyrus and CA3 regions of HS and non-HS groups. The lack of any differences in expression levels was observed between HS and non-HS patients. Meanwhile, treatment with VPA (Valproic acid, anti-epileptic drug) resulted in a significant down-regulation of BDNF/trkB protein expression in sclerotic and non-sclerotic hippocampus (P < 0.001). In contrast, no marked change was noticed in VPA-untreated and OA-treated groups (sodium octanoate). Conclusion : These results suggest that the up-regulation of BDNF/trkB pathway might be at least in part responsible for the epileptogenesis.


Keywords: Brain-derived neurotrophic factor, tyrosine kinase receptor B, temporal lobe epilepsy, valproic acid, hippocampal sclerosis, epileptogenesis


How to cite this article:
Hou X, Wang X, Zhang L. Conditional downregulation of brain- derived neurotrophic factor and tyrosine kinase receptor B blocks epileptogenesis in the human temporal lobe epilepsy hippocampus. Neurol India 2010;58:29-34

How to cite this URL:
Hou X, Wang X, Zhang L. Conditional downregulation of brain- derived neurotrophic factor and tyrosine kinase receptor B blocks epileptogenesis in the human temporal lobe epilepsy hippocampus. Neurol India [serial online] 2010 [cited 2020 Apr 2];58:29-34. Available from: http://www.neurologyindia.com/text.asp?2010/58/1/29/60392



 » Introduction Top


Temporal lobe epilepsy (TLE) is a common, complex disorder, with heterogeneous clinical manifestations and multiple genetic and non-genetic factors. [1] The hippocampus in many individuals with TLE is characterized by cell loss in specific regions, most prominently in CA1 and CA3, a pattern termed hippocampal (or mesial temporal) sclerosis (HS). [2] Morphological investigation of resected tissue has revealed that while one group of TLE is associated with HS characterized by segmental or total cell loss and aberrant mossy fiber sprouting, especially in the CA1 and CA3 areas and dentate hilus regions of the hippocampus, [3],[4] another group is associated with less segmental cell loss (non-HS). Mossy fiber sprouting in the dentate gyrus may be a factor in the pathogenesis of TLE. It has been hypothesized that TLE arises out of the loss of hilar neurons and subsequent deafferentation of the inner molecular layer. [5],[6],[7] Neurotrophic factors may be required to initiate exuberant synapses and therefore may be important for the process of epileptogenesis.

One target of the responsible factors is the brain- derived neurotrophic factor (BDNF), a member of the neurotrophin family, which is highly expressed in many areas of the central nervous system (CNS) and is critically involved in synaptic plasticity, membrane excitability and neurotransmission. [8] Studies on hippocampal slices have indicated that BDNF can potentiate excitatory transmission, probably by a presynaptic mechanism mediated by tyrosine kinase receptor B (trkB). [9] Furthermore, while BDNF increases excitation and decreases inhibition in the brain, seizures can induce an up-regulation of both BDNF and trkB receptors. [10]

Valproic acid (VPA) is a short-chain, branched fatty acid with broad-spectrum anticonvulsant activity. VPA treatment potently protected epileptic animals from hippocampus-dependent cognitive impairment after kainic acid-induced seizures. [11] To investigate the implicated role of BDNF in TLE, we examined the expression of BDNF and trkB in hippocampi of patients with TLE. We also tested whether VPA would influence BDNF and trkB expression, especially in HS and non-HS, which might be at least in part responsible for preventing the epileptogenesis.


 » Materials and Methods Top


Patient selection and tissue collection

This study was performed between January 2006 and December 2007 on hippocampal tissue obtained from 40 patients suffering from pharmaco-resistant TLE as determined by the First Affiliated Hospital of Harbin Medical University, according to the criteria of the International League Against Epilepsy (ILAE) classification for presurgical evaluation. [12] This study was approved by the ethics committee of the First Affiliated Hospital of Harbin Medical University (China), and a written informed consent for the study was obtained from each patient. All patients were assessed by comprehensive epilepsy testing, including clinical characterization, Video-electroencephalogram (VEEG), psychiatric and neuropsychological assessments. Hippocampal sclerosis was defined if visual inspection of magnetic resonance imaging (MRI) pictures revealed both hippocampal atrophy and T2 signal abnormalities, and then identified by microscopic analysis by an experienced neuropathologist using neuronal loss in a characteristic pattern (most severe in area CA1 and the dentate hilus) as the criteria. [13] Patients with bilateral HS or dual pathology (HS accompanied by other epileptogenic lesion) were excluded. After en bloc resection, the hippocampus was microdissected into subregions and total protein was extracted from the CA3 and dentate gyrus subregions. Tissue samples for immunohistochemistry were immediately fixed in 4% formaldehyde and 15% saturated picric acid (pH 7.4) overnight at room temperature and embedded in paraffin. Samples for immunoblotting were freshly frozen on dry ice and stored at -80 °C until further use. Normal hippocampal tissue samples were obtained from the brain storeroom of the First Affiliated Hospital of Harbin Medical University as experimental controls. Ten samples were used for immunohistochemistry study, and ten samples (death due to cerebral trauma, cancer of pancreas, congestive heart disease, acute hepatic failure) for the Western-blot analysis. Considering that trauma increases the expression of BDNF, only one sample was derived from the cerebral trauma.

For pharmacological studies, hippocampal specimens from surgery were immediately transferred into cold sucrose solution containing the following (in mM) 234 sucrose, 11 glucose, 24 NaHCO 3 , 2.5 KCl, 1.25 NaH 2 PO 4 , 2 MgSO 4 , and 0.5 CaCl 2 , equilibrated with a 95%-5% mixture of O 2 and CO 2 . Horizontal slices (400 µm) were cut on a VT 1000S Vibratome (Leica, Bensheim, Germany) at 4°C in sucrose solution. Hippocampal specimens were immediately immersed in sucrose solution containing sodium valproate (VPA; Sigma, 0.3 mM, similar to the therapeutic dose) or its pharmacologically inactive analog, sodium octanoate (OA; Sigma) for 3 h (hours) or 9 h. Slices were thereafter stored at -80°C for Western - blot analysis.

Histology and histochemistry

Fixed slices were incubated in phosphate-buffered-saline (PBS, 0.01M) containing 10% methanol and 3% H 2 O 2 for 1 h then incubated in avidin-biotin-horseradish peroxidase complex (ABC Elite kit; Vector laboratories Inc, Burlingame, CA) in PBS (1:100; pH 7.3) containing 2% Triton X for 48 to 72 h at 4°C. The slices were then reacted with 3, 3'-diaminobenzidine tetrahydrochloride (0.06%) and H 2 O 2 (0.003%) in PBS (pH 7.4). Sections were fixed and stained with hematoxylin and eosin (HE).

Immunohistochemistry

To test the expression of BDNF and trkB in patients with TLE, immunohistochemical staining was first performed on different groups. The different subareas in the hippocampus were defined according to the nomenclature of Amaral and Insausti. [14] Selected hippocampal subareas for analysis were: CA1, CA2, CA3, hilus, and dentate gyrus. Three-micron-thick slices were washed three times, for 10 min each, in 0.1 M and endogenous peroxidase activity blocked with 3% H 2 O 2 . Tissue sections from all patients were stained simultaneously to minimize variation in the immunohistochemical reactions. Afterwards, sections were incubated in one of the primary antibody solutions (BDNF, 1:200 and trkB 1:150, respectively; SANTA CRUZ, CA, USA), overnight at 4°C. [15] After three washes in 0.1 M PBS for 5 min each, sections were incubated with secondary antibodies (goat anti-rabbit IgG, 1:200 dilution; Vector Laboratories, Burlingame, CA). The resultant immuno peroxidase complexes were developed by incubation in 0.5% 3, 3'-diaminobenzidine hydrochloride (DAB; Sigma, Saint Louis, MO, USA) in PBS. For each antibody, control experiments were performed in which the primary antibody was omitted.

The results of the immunohistochemical staining were read separately by two pathologists who were blinded to the clinical parameters of the individual cases. BDNF and trkB immunostaining showed brown coloration of plasma and nuclei indicating positive staining. Unstained plasma and nuclei took blue color. The score of BDNF and trkB = Number of cells showing positive staining/Total number of cells x 100%. The number of BDNF and trkB expressing positive cells was estimated as a percentage of the total number of cells per section and scored in four categories: 0, < 5%; 1, 5-25%; 2, 26-50%; 3, >50%. The intensity of staining was graded such that negative control, (score 0), weak staining, (score 1), moderate staining, (score 2), strong staining, (score 3). Then score of percentage of cells stained and the intensity of cell staining were combined such that: A score of 0 was (-), a score of 1 was (±), a score of 2-3 was (+), a score of 4-6 was (++), and a score of 7-9 was (+++).

Western blot analysis

Fresh hippocampal specimens were lysed on ice for 10 min in a lysis buffer (400 mM KCl, 50 mM HEPES, 1.5 mM EDTA, 20% glycerol, 0.5% NP 4 O, 20 mM NaF, 10 mM Na 2 molybdate, 10 µM Na 3 ortho, and 1 mM dithiothreitol) containing a mixture of protease inhibitors (1 mM PMSF, 0.2 mg/ml bacitracin, 0.2 mg/ml aprotin, 5 µg/ml leupeptin, and 5 µg/ml pepstatin A). Specimens were then homogenized and centrifuged at 1000 x g for 30 min. Protein concentrations were determined by the Bradford method. The supernatant was boiled for 8 min in 2 x SDS sample buffer (62.5 M Tris-HCl, 10% glycerol, 2% SDS, 0.05% bromphenol blue, 1% ß-mercaptoethanol) and centrifuged at 1000 x g for 1 min at 4°C. Samples were electrophoresed on 15% SDS polyacrylamide gels, transferred onto nitrocellulose membrane using a semi-dry system at 24 V for 435 min. Membranes were stained by Ponceau S, nonspecific binding blocked by 0.02 mM PBS containing 5% skim milk and 0.05% Tween-20 for 1 h, incubated overnight with affinity-purified rabbit polyclonal antibody for BDNF (1:200 dilution) and trkB (1:150 dilution) in the same buffer solution. After three 10-min washes in PBS, the membrane was incubated with a horseradish peroxidase-conjugated anti-rabbit IgG (1:6000 dilution; Promega Corporation, Madison,Wisconsin, USA) for 1 h. Following a 30 min rinse with buffer, immunoreactive bands were dried and visualized by enhanced chemiluminescence in the dark for 30 min, using a stabilized substrate for alkaline phosphatase (Promega Corporation, Madison, Wisconsin, USA).

Statistical analysis

Data are expressed as mean ± standard deviation of values. Statistical analyses were performed using the One-way ANOVA, Chi-squared test and Wilcoxon rank sum test. Densitometric measurements were analyzed for significant group differences using one-way ANOVA. A value of P < 0.05 was considered statistically significant. Data were analyzed by SAS 8.2 software package (SAS Institute Inc., Cary, North Carolina, USA) and the program for one-way Anova test in SAS is proc anova; the program for Chi-squared test is proc freq; and the program for Wilcoxon rank sum test is proc npar1way Wilcoxon.


 » Results Top


The clinical characteristics of the control and TLE patients (HS and non-HS) are summarized in [Table 1]. Forty patients fulfilled the inclusion criteria. HS was assessed in 20 patients (28.5 ± 8.7 years of age); 20 patients were assessed to be non-HS (22.2 ± 9.3 years of age). The mean duration of epilepsy was 14.7 ± 9.8 years in HS patients and 11.0 ± 7.1 years in non-HS patients. There were no differences between HS and non-HS patients with regard to the side (right or left) of resection, age and gender (P > 0.05).

Increased expression of brain-derived neurotrophic factor and tyrosine kinase receptor B in patients with temporal lobe epilepsy

To assess the expression levels of BDNF and trkB in the patients with TLE in comparison with controls, an immunohistochemical study was performed. In the hippocampal tissue, an increase of BDNF immunoreactivity was evident in the cytoplasm and proximal dendrites of CA3 pyramidal neurons [Figure 1]. In addition, increases of trkB immunoreactivity have been present in cytoplasm and nucleolus. Meanwhile, the glial cells as identified by glial fibrillary acidic protein (GFAP) staining in adjacent sections were negative for BDNF and trkB.

The control group displayed low level of BDNF immunoreactivity. In the TLE group (HS and non-HS), however, a significant increase in BDNF was observed in dentate gyrus compared with the control hippocampus (P < 0.01, [Table 2]). Similar results were observed in the CA3 region (data not shown). trkB displayed a similar immunoreactivity distribution. Quantification of BDNF and trkB revealed a robust increase in the HS and non-HS group compared with the control group. However, there was no statistically significant difference between the HS and non-HS groups (P >0.05, [Table 2]).

Elevated brain-derived neurotrophic factor and tyrosine kinase receptor B protein levels in temporal lobe epilepsy patients

To assess whether comparable changes in protein product levels of BDNF and trkB occurred in the hippocampus, a semiquantitative analysis was carried out by Western-blotting. A drastic increase in BDNF and trkB proteins was observed in the dentate gyrus [Figure 2]a and CA3 regions (data not shown) of the TLE group. Results for the hippocampal tissues were consistent with immunohistochemical analysis [Figure 2], showing a significant increase of BDNF protein (14 KDa) in the HS and non-HS groups. Meanwhile, trkB levels were significantly up-regulated (145 KDa) compared with the control group ( P < 0.05). There were no obvious differences between the HS and non-HS groups ( P >0.05, [Figure 2]b).

Valproic acid treatment results in down-regulated brain-derived neurotrophic factor and tyrosine kinase receptor B protein levels

We tested the hypothesis that VPA treatment leads to the decrease of BDNF and trkB expression and explored the mechanism relating to the increase of BDNF and trkB in epileptogenic patients. Because BDNF synthesis would require time to change, 1 h VPA incubation did not produce any significant changes in BDNF expression, VPA (0.3 mM) decreased BDNF expression by 39% and 53% in HS and non-HS patients at 3 h, respectively, and 85% and 77% at 9 h compared with the VPA-untreated group (control). The levels of trkB attenuated 3.7 and 2.0 fold by 3 h and 6.4 and 5.0-fold by 9 h of VPA treatment compared with OA-treated and control groups (P < 0.001, [Figure 3]b). In contrast, changes of BDNF and trkB protein were not evident between the HS and non-HS group (P = 0.15, [Figure 3]b).


 » Discussion Top


The majority of patients with TLE have HS as a pathological abnormality underlying TLE. Surgical resection of the epileptogenic tissue, in particular the hippocampus, most often results in seizure control, implicating the hippocampus in the generation and propagation of seizures in these patients. [16] In hippocampal specimens of patients with HS, the mossy fibers send collaterals into the inner molecular layer of the dentate gyrus and form multiple asymmetric synapses with the dendritic structures of granule cells. [17]

Seizure-induced up-regulation of BDNF [18],[19] in the hippocampus is a common phenomenon across various experimental models of epilepsy. Studies from areas CA1 and CA3 in hippocampal slices have indicated that BDNF can potentiate excitatory transmission, probably by a presynaptic mechanism mediated by trkB receptors. [20] A similar mechanism is also implicated in the dentate gyrus. [21] However, the evidence for specific contributions of BDNF and trkB to TLE (HS and non-HS) remains controversial. Some studies have revealed that in comparison with non-HS cases, patients with HS show increased BDNF, nervre growth factor(NGF) and NT-3 mRNA. [22] Moreover, granule cell BDNF mRNA levels correlated inversely with neuronal density in the Ammon's horn and correlated positively with supragranular mossy fiber sprouting. These results indicate that in the chronically damaged human hippocampus, granule cells express neurotrophin mRNAs, and that the mRNA levels correlate with either neuronal loss in the hippocampus or aberrant supragranular mossy fiber sprouting. However, the present study shows obviously up-regulated BDNF and trkB immunoreactivity in the hippocampal neurons (dentate gyrus and CA3), with no pronounced differences in intensity between the HS and non-HS groups. Consistent with our immunohistochemical data, BDNF and trkB were significantly up-regulated in hippocampal tissue from the HS and non-HS groups compared with the control group. VPA is used to treat epilepsy. It alters gene transcription, through the inhibition of histone deacetylase and the activation of transcription factors and signaling cascades. [23],[24] The results presented here demonstrate significant down-regulation of BDNF and trkB protein expression in the hippocampal regions of patients with HS and non-HS TLE. In contrast to the VPA-treated group, no marked change was noticed in VPA-untreated or OA-treated groups, indicating that BDNF-mediated activation of trkB enhances the excitatory actions on hippocampi of TLE patients.

A large body of evidence suggests that BDNF is involved in TLE, although it is not entirely clear whether its function is pro-epileptogenic or anti-epileptogenic. In human subjects with epilepsy, BDNF and other neurotrophins have been reported to play a role in morphological changes leading to hyperexcitability of the hippocampus. In particular, BDNF and nerve growth factor mRNA levels are increased in kindling and other seizure models, whereas NT-3 mRNA level is decreased. The increased neuronal activity leads to a secondary increase in BDNF/trkB levels and initiates further potentiation. [25] Recent studies have shown that interfering with BDNF signal transduction inhibits the development of the epileptic state in vivo[26] and infusion of BDNF into hippocampus is followed by seizures. [27] These events ultimately would escalate by positive feedback and reach seizure threshold. [28] Our main contribution to this topic is the finding that drastic attenuation of BDNF/trkB levels occurs in the hippocampus when treated by VPA, implying the presence of BDNF-evoked excitatory synaptic currents in human TLE hippocampus.


 » Conclusion Top


The significant elevation of BDNF/trkB expression levels, in sclerotic and non-sclerotic hippocampal specimens suggests that epileptogenecity is promoted by BDNF activation of trkB. Further studies on the mechanism by which VPA regulates the function of BDNF/trkB in TLE patients are essential for a better understanding of human epilepsy.


 » Acknowledgments Top


We wish to thank Rui Re, Ben-chang Li (Harbin Medical University) for technical assistance. This work was supported by Grants-in-aid for Science Foundation of Heilongjiang province of China (GB06C40307).

 
 » References Top

1.Scharfman HE, Pedley TA. Temporal lobe epilepsy. In: Gilman S, editor. The neurobiology of disease. New York: Academic Press; 2006. p. 349-70.  Back to cited text no. 1      
2.Mathern GW, Babb TL, Armstrong DL. Hippocampal sclerosis. In: Epilepsy: A comprehensive textbook/Engel J Jr, Pedley TA, editors. Philadelphia: Lippincott-Raven; 1997. p. 133-55.  Back to cited text no. 2      
3.Dudek FE, Sutula TP. Epileptogenesis in the dentate gyrus: A critical perspective. Prog Brain Res 2007;163:755-73.  Back to cited text no. 3      
4.Sutula TP, Dudek FE. Unmasking recurrent excitation generated by mossy fiber sprouting in the epileptic dentate gyrus: An emergent property of a complex system. Prog Brain Res 2007;163:541-63.  Back to cited text no. 4      
5.Einat H, Yuan P, Gould TD, Li J, Du J, Zhang L, et al. The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J Neurosci 2003;23:7311-6.  Back to cited text no. 5      
6.Pirttilä TJ, Manninen A, Jutila L, Nissinen J, Kälviäinen R, Vapalahti M, et al. Cystatin C expression is associated with granule cell dispersion in epilepsy. Ann Neurol 2005;58:211-23.  Back to cited text no. 6      
7.Brandt C, Ebert U, Löscher W. Epilepsy induced by extended Amygdala-kindling in rats: Lack of clear association between development of spontaneous seizures and neuronal damage. Epilepsy Res 2004;62:135-56.  Back to cited text no. 7      
8.Youssoufian M, Walmsley B. Brain-derived neurotrophic factor modulates cell excitability in the mouse medial nucleus of the trapezoid body. Eur J Neurosci 8. 2007;25:1647-52.  Back to cited text no. 8      
9.Takei N, Sasaoka K, Inoue K, Takahashi M, Endo Y, Hatanaka H. Brain-derived neurotrophic factor increases the stimulation-evoked release of glutamate and the levels of exocytosis-associated proteins in cultured cortical neurons from embryonic rats. J Neurochem 1997;68:370-5.  Back to cited text no. 9      
10.Koyama R, Yamada MK, Fujisawa S, Katoh-Semba R, Matsuki N, Ikegaya Y. Brain-derived neurotrophic factor induces hyperexcitable reentrant circuits in the dentate gyrus. Neuroscience 2004;24:7215-24.  Back to cited text no. 10      
11.Jessberger S, Nakashima K, Clemenson GD Jr, Mejia E, Mathews E, Ure K, et al. Epigenetic modulation of seizure-induced neurogenesis and cognitive decline. J Neursci 2007;27:5967-75.  Back to cited text no. 11      
12.Wiebe S. Epidemiology of temporal lobe epilepsy. Can J Neurol Sci 2000;27:6-10.  Back to cited text no. 12      
13.Mathern GW, Babb TL, Vickrey BG, Melendez M, Pretorius JK. The clinical-pathogenic mechanisms of hippocampal neuron loss and surgical outcomes in temporal lobe epilepsy. Brain 1995;118:105-18.  Back to cited text no. 13      
14.Amaral DG, Insausti R. Hippocampal formation. In: Paxinos G, editor. The humannervous system. San Diego: Academic Press; 1990. p. 711-55.  Back to cited text no. 14      
15.Tongiorgi E, Armellin M, Giulianini PG, Bregola G, Zucchini S, Paradiso B, et al. Brain-derived neurotrophic factor mRNA and proteins are targeted to discrete dendritic laminas by events that trigger epileptogenesis. J Neurosci 2004;24:6842-52.  Back to cited text no. 15      
16.Ang CW, Carlson GC, Coulter DA. Massive and specific dysregulation of direct cortical input to the hippocampus in temporal lobe epilepsy. J Neurosci 2006;26:11850-6.  Back to cited text no. 16      
17.Proper EA, Oestreicher AB, Jansen GH, Veelen CW, van Rijen PC, Gispen WH, et al. Immunohistochemical characterization of mossy fibre sprouting in the hippocampus of patients with pharmaco-resistant temporal lobe epilepsy. Brain 2000;123:19-30.  Back to cited text no. 17      
18.Danzer SC, He X, McNamara JO. Ontogeny of seizure-induced increases in BDNF immunoreactivity and TrkB receptor activation in rat hippocampus. Hippocampus 2004;14:345-55.  Back to cited text no. 18      
19.Foster JA, Puchowicz MJ, McIntyre DC, Herkenham M. Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures. J Comp Neurol 2004;476:91-102.  Back to cited text no. 19      
20.Yagasaki Y, Numakawa T, Kumamaru E, Hayashi T, Su TP, Kunugi H. Chronic antidepressants potentiate via sigma-1 receptors the brain-derived neurotrophic factor-induced signaling for glutamate release. J Biol Chem 2006;281:12941-9.  Back to cited text no. 20      
21.Scharfman HE. Hyperexcitability in combined entorhinal/hippocampal slices of adult rat after exposure to brain-derived neurotrophic factor. J Neurophysiol 1997;78:1082-95.  Back to cited text no. 21      
22.Scharfman HE, Goodman JH, Sollas AL. Actions of brain-derived neurotrophic factor in slices from rats with spontaneous seizures and mossy fiber sprouting in the dentate gyrus. J Neurosci 1999;19:5619-31.  Back to cited text no. 22      
23.Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid: A potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 2001;276:36734 -41.  Back to cited text no. 23      
24.Arif H, Buchsbaum R, Weintraub D, Koyfman S, Salas-Humara C, Bazil CW, et al. Comparison and predictors of rash associated with 15 antiepileptic drugs. Neurology 2007;68:1701-9.  Back to cited text no. 24      
25.Mudo G, Jiang XH, Timmusk T, Bindoni M, Belluardo N. Change in neurotrophins and their receptor mRNAs in the rat forebrain after status epilepticus induced by pilocarpine. Epilepsia 1991;37:198-207.  Back to cited text no. 25      
26.Binder DK, Croll SD, Gall CM, Scharfman HE. BDNF and epilepsy: Too much of a good thing? Trends Neurosci 2001;24:47-53.  Back to cited text no. 26      
27.Scharfman HE, Goodman JH, Sollas AL, Croll SD. Spontaneous limbic seizures after intrahippocampal infusion of brain-derived neurotrophic factor. Exp Neurol 2002;174:201-14.  Back to cited text no. 27      
28.Scharfman HE. Brain-derived neurotrophic factor and epilepsy: A missing link? Epilepsy Curr 2005;5:83-8.  Back to cited text no. 28      


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]

This article has been cited by
1 Increased Expression of Brain-Derived Neurotrophic Factor Transcripts I and VI, cAMP Response Element Binding, and Glucocorticoid Receptor in the Cortex of Patients with Temporal Lobe Epilepsy
G. A. Martínez-Levy,L. Rocha,F. Rodríguez-Pineda,M. A. Alonso-Vanegas,A. Nani,R. M. Buentello-García,M. Briones-Velasco,D. San-Juan,J. Cienfuegos,C. S. Cruz-Fuentes
Molecular Neurobiology. 2017;
[Pubmed] | [DOI]
2 Glucagon-like Peptide-1 (GLP-1) and neurotransmitters signaling in epilepsy: An insight review
Prashant Koshal,Sumit Jamwal,Puneet Kumar
Neuropharmacology. 2017;
[Pubmed] | [DOI]
3 Increased expression of BDNF transcript with exon VI in hippocampi of patients with pharmaco-resistant temporal lobe epilepsy
G.A. Martínez-Levy,L. Rocha,F.D. Lubin,M.A. Alonso-Vanegas,A. Nani,R.M. Buentello-García,R. Pérez-Molina,M. Briones-Velasco,F. Recillas-Targa,A. Pérez-Molina,D. San-Juan,J. Cienfuegos,C.S. Cruz-Fuentes
Neuroscience. 2016; 314: 12
[Pubmed] | [DOI]
4 Seizure control by ketogenic diet-associated medium chain fatty acids
Chang, P. and Terbach, N. and Plant, N. and Chen, P.E. and Walker, M.C. and Williams, R.S.B.
Neuropharmacology. 2013; 69: 105-114
[Pubmed]
5 Seizure control by ketogenic diet-associated medium chain fatty acids
Pishan Chang,Nicole Terbach,Nick Plant,Philip E. Chen,Matthew C. Walker,Robin S.B. Williams
Neuropharmacology. 2013; 69: 105
[Pubmed] | [DOI]
6 Selective upregulation of brain-derived neurotrophic factor (BDNF) transcripts and BDNF direct induction of activity independent N-methyl-D-aspartate currents in temporal lobe epilepsy patients with hippocampal sclerosis
Wang, F.J., Li, C.M., Hou, X.H., Wang, X.R., Zhang, L.M.
Journal of International Medical Research. 2011; 39(4): 1358-1368
[Pubmed]
7 The effects of low frequency repetitive transcranial magnetic stimulation on the rat model of refractory epilepsy and expression of brain - Derived neurotrophic factor and neuropeptide Y
Zhang, L., Wu, S., Tao, H., Zhang, X.
Chinese Journal of Contemporary Neurology and Neurosurgery. 2011; 11(4): 428-433
[Pubmed]
8 Selective Upregulation of Brain-Derived Neurotrophic Factor (BDNF) Transcripts and BDNF Direct Induction of Activity Independent N-Methyl-D-Aspartate Currents in Temporal Lobe Epilepsy Patients with Hippocampal Sclerosis
FJ Wang,CM Li,XH Hou,R Wang,LM Zhang
Journal of International Medical Research. 2011; 39(4): 1358
[Pubmed] | [DOI]
9 Brain-derived neurotrophic factor expression is higher in brain tissue from patients with refractory epilepsy than in normal controls
Lv, Y. and Qiu, J. and Wang, Z. and Cui, L. and Meng, H. and Lin, W.
Neural Regeneration Research. 2011; 6(29): 2262-2266
[Pubmed]
10 Prevention or modification of epileptogenesis after brain insults: Experimental approaches and translational research
Löscher, W., Brandt, C.
Pharmacological Reviews. 2010; 62(4): 668-700
[Pubmed]



 

Top
Print this article  Email this article
Previous article Next article
Online since 20th March '04
Published by Wolters Kluwer - Medknow