Seizure-Suppressant and Neuroprotective Effects of Encapsulated BDNF-Producing Cells in a Rat Model of Temporal Lobe Epilepsy

Brain-derived neurotrophic factor (BDNF) may represent a therapeutic for chronic epilepsy, but evaluating its potential is complicated by difficulties in its delivery to the brain. Here, we describe the effects on epileptic seizures of encapsulated cell biodelivery (ECB) devices filled with genetically modified human cells engineered to release BDNF. These devices, implanted into the hippocampus of pilocarpine-treated rats, highly decreased the frequency of spontaneous seizures by more than 80%. These benefits were associated with improved cognitive performance, as epileptic rats treated with BDNF performed significantly better on a novel object recognition test. Importantly, long-term BDNF delivery did not alter normal behaviors such as general activity or sleep/wake patterns. Detailed immunohistochemical analyses revealed that the neurological benefits of BDNF were associated with several anatomical changes, including reduction in degenerating cells and normalization of hippocampal volume, neuronal counts (including parvalbumin-positive interneurons), and neurogenesis. In conclusion, the present data suggest that BDNF, when continuously released in the epileptic hippocampus, reduces the frequency of generalized seizures, improves cognitive performance, and reverts many histological alterations associated with chronic epilepsy. Thus, ECB device-mediated long-term supplementation of BDNF in the epileptic tissue may represent a valid therapeutic strategy against epilepsy and some of its co-morbidities.

[1]  W. Lanksch,et al.  Alterations of Neuronal Connectivity in Area CA1 of Hippocampal Slices from Temporal Lobe Epilepsy Patients and from Pilocarpine‐Treated Epileptic Rats , 2000, Epilepsia.

[2]  Eric Westman,et al.  Changes in CSF cholinergic biomarkers in response to cell therapy with NGF in patients with Alzheimer's disease , 2015, Alzheimer's & Dementia.

[3]  Michael Söderman,et al.  Targeted delivery of nerve growth factor via encapsulated cell biodelivery in Alzheimer disease: a technology platform for restorative neurosurgery. , 2012, Journal of neurosurgery.

[4]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[5]  Gorka Orive,et al.  Encapsulated cell therapy for neurodegenerative diseases: from promise to product. , 2014, Advanced drug delivery reviews.

[6]  M. Greenberg,et al.  New Insights in the Biology of BDNF Synthesis and Release: Implications in CNS Function , 2009, The Journal of Neuroscience.

[7]  R. Racine Modification of seizure activity by electrical stimulation: cortical areas. , 1975, Electroencephalography and clinical neurophysiology.

[8]  G. Schulte,et al.  Brain‐derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast‐spiking GABAergic interneurons , 2004, The European journal of neuroscience.

[9]  Manju Sasi,et al.  Neurobiology of local and intercellular BDNF signaling , 2017, Pflügers Archiv - European Journal of Physiology.

[10]  William C. Wetsel,et al.  Transient Inhibition of TrkB Kinase after Status Epilepticus Prevents Development of Temporal Lobe Epilepsy , 2013, Neuron.

[11]  F. Angelucci,et al.  Mapping the differences in the brain concentration of brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in an animal model of depression , 2000, Neuroreport.

[12]  G. Sperk,et al.  Parvalbumin interneurons and calretinin fibers arising from the thalamic nucleus reuniens degenerate in the subiculum after kainic acid-induced seizures , 2011, Neuroscience.

[13]  E. Magri,et al.  Localized delivery of fibroblast growth factor–2 and brain-derived neurotrophic factor reduces spontaneous seizures in an epilepsy model , 2009, Proceedings of the National Academy of Sciences.

[14]  M. Walker,et al.  Opportunities for improving animal welfare in rodent models of epilepsy and seizures , 2016, Journal of Neuroscience Methods.

[15]  D. Prince,et al.  Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis , 2017, Neurobiology of Disease.

[16]  E. Tongiorgi,et al.  What is the biological significance of BDNF mRNA targeting in the dendrites? , 2006, Molecular Neurobiology.

[17]  E. Ellinwood,et al.  Rating the behavioral effects of amphetamine. , 1974, European journal of pharmacology.

[18]  E. Magri,et al.  Impairment of GABA release in the hippocampus at the time of the first spontaneous seizure in the pilocarpine model of temporal lobe epilepsy , 2014, Experimental Neurology.

[19]  D. Emerich,et al.  Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer , 2011, Gene Therapy.

[20]  M. Kameda,et al.  BDNF-secreting capsule exerts neuroprotective effects on epilepsy model of rats , 2011, Brain Research.

[21]  R. Miledi,et al.  GABAA-current rundown of temporal lobe epilepsy is associated with repetitive activation of GABAA “phasic” receptors , 2007, Proceedings of the National Academy of Sciences.

[22]  B. Paradiso,et al.  Localized overexpression of FGF‐2 and BDNF in hippocampus reduces mossy fiber sprouting and spontaneous seizures up to 4 weeks after pilocarpine‐induced status epilepticus , 2011, Epilepsia.

[23]  David R Kaplan,et al.  Neurotrophin signal transduction in the nervous system , 2000, Current Opinion in Neurobiology.

[24]  F. Jensen,et al.  The challenge and promise of anti-epileptic therapy development in animal models , 2014, The Lancet Neurology.

[25]  W. Löscher,et al.  Treatment with valproate after status epilepticus: Effect on neuronal damage, epileptogenesis, and behavioral alterations in rats , 2006, Neuropharmacology.

[26]  H. Mount,et al.  Object recognition memory and BDNF expression are reduced in young TgCRND8 mice , 2012, Neurobiology of Aging.

[27]  Jatinder Singh,et al.  The national centre for the replacement, refinement, and reduction of animals in research , 2012, Journal of pharmacology & pharmacotherapeutics.

[28]  Bruce Hermann,et al.  The neurobehavioural comorbidities of epilepsy: can a natural history be developed? , 2008, The Lancet Neurology.

[29]  J. McNamara,et al.  A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus , 2015, Neuron.

[30]  M. Kokaia,et al.  Angels and demons: neurotrophic factors and epilepsy. , 2006, Trends in pharmacological sciences.

[31]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[32]  R. Miledi,et al.  BDNF modulates GABAA receptors microtransplanted from the human epileptic brain to Xenopus oocytes. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[33]  G. Holmes,et al.  Cognitive and Behavioral Co-Morbidities of Epilepsy , 2012 .

[34]  M. Cammarota,et al.  BDNF controls object recognition memory reconsolidation , 2017, Neurobiology of Learning and Memory.

[35]  R. Scott Network science for the identification of novel therapeutic targets in epilepsy , 2016, F1000Research.

[36]  J. DeFelipe,et al.  Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus , 2007, Neuroscience.

[37]  O. Sporns,et al.  Network neuroscience , 2017, Nature Neuroscience.

[38]  H. Scharfman,et al.  Mini Review , 2004 .

[39]  T. Harkany,et al.  Selective Silencing of Hippocampal Parvalbumin Interneurons Induces Development of Recurrent Spontaneous Limbic Seizures in Mice , 2017, The Journal of Neuroscience.

[40]  D. Atanasova,et al.  Agomelatine protects against neuronal damage without preventing epileptogenesis in the kainate model of temporal lobe epilepsy , 2017, Neurobiology of Disease.

[41]  R. S. Sloviter The neurobiology of temporal lobe epilepsy: too much information, not enough knowledge. , 2005, Comptes rendus biologies.

[42]  D. Geschwind,et al.  Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease , 2009, Nature Medicine.

[43]  Douglas G Altman,et al.  Animal Research: Reporting in vivo Experiments—The ARRIVE Guidelines , 2011, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.