Citicoline increases glutathione redox ratio and reduces caspase-3 activation and cell death in staurosporine-treated SH-SY5Y human neuroblastoma cells

Citicoline, or CDP-choline, is an essential endogenous intermediate in the biosynthesis of phosphatidylcholine that may act as a neuroprotector in several models of neurodegeneration. The present study analyses the effects of citicoline in the paradigm of staurosporine-induced cell death in human SH-SY5Y neuroblastoma cells. Citicoline reduces apoptosis induced by 100 nM staurosporine for 12 h in SH-SY5Y cells. This effect is higher with pre-treatment of 60 mM citicoline for 24 h after staurosporine challenge. Moreover, citicoline treatment restores glutathione redox ratio diminished after staurosporine challenge. Finally, citicoline also reduces the expression levels of active caspase-3 and specific PARP-cleaved products of 89 kDa resulting from staurosporine exposure when citicoline is added to the culture medium 24 h before staurosporine. These findings demonstrate that citicoline affects the staurosporine-induced apoptosis cell-signalling pathway by interacting with the glutathione system and by inhibiting caspase-3 in SH-SY5Y human neuroblastoma cells.     

Oestradiol and Insulin‐Like Growth Factor‐1 Reduce Cell Loss after Global Ischaemia in Middle‐Aged Female Rats

Whereas the ability of oestradiol and insulin‐like growth factor (IGF)‐1 to afford neuroprotection against ischaemia‐induced neuronal death in young female and male rodents is well established, the impact of IGF‐1 in middle‐aged animals is largely unknown. The present study assessed the efficacy of oestradiol and IGF‐1 with respect to reducing neuronal death after transient global ischaemia in middle‐aged female rats after 8 weeks of hormone withdrawal. Rats were ovariohysterectomised and implanted 8 weeks later with an osmotic mini‐pump delivering IGF‐1 or saline into the lateral ventricle. Some rats also received physiological levels of oestradiol by subcutaneous pellet. Two weeks later, rats were subjected to global ischaemia or sham operation. Surviving hippocampal CA1 neurones were quantified. Ischaemia produced massive CA1 cell death compared to sham‐operated animals, which was evident at 14 days. Significantly more neurones survived in animals treated with either oestradiol or IGF‐1, but simultaneous treatment produced no additive effect. IGF‐1, an endogenous growth factor, may be a clinically useful therapy in preventing human brain injury, with neuroprotective equivalence to oestradiol but without the harmful side‐effects.     

DPP4‐inhibitor improves neuronal insulin receptor function,brain mitochondrial function and cognitive function in rats with insulin resistance induced by high‐fat diet consumption

High‐fat diet (HFD) consumption has been demonstrated to cause peripheral and neuronal insulin resistance, and brain mitochondrial dysfunction in rats. Although the dipeptidyl peptidase‐4 inhibitor, vildagliptin, is known to improve peripheral insulin sensitivity, its effects on neuronal insulin resistance and brain mitochondrial dysfunction caused by a HFD are unknown. We tested the hypothesis that vildagliptin prevents neuronal insulin resistance, brain mitochondrial dysfunction, learning and memory deficit caused by HFD. Male rats were divided into two groups to receive either a HFD or normal diet (ND) for 12 weeks, after which rats in each group were fed with either vildagliptin (3 mg/kg/day) or vehicle for 21 days. The cognitive function was tested by the Morris Water Maze prior to brain removal for studying neuronal insulin receptor (IR) and brain mitochondrial function. In HFD rats, neuronal insulin resistance and brain mitochondrial dysfunction were demonstrated, with impaired learning and memory. Vildagliptin prevented neuronal insulin resistance by restoring insulin‐induced long‐term depression and neuronal IR phosphorylation, IRS‐1 phosphorylation and Akt/PKB‐ser phosphorylation. It also improved brain mitochondrial dysfunction and cognitive function. Vildagliptin effectively restored neuronal IR function, increased glucagon‐like‐peptide 1 levels and prevented brain mitochondrial dysfunction, thus attenuating the impaired cognitive function caused by HFD.     

Pharmacodynamics of citicoline relevant to the treatment of glaucoma.

Citicoline (exogenous CDP-choline) is a nontoxic and well-tolerated drug used in pharmacotherapy of brain insufficiency and some other neurological disorders, such as stroke, brain trauma, and Parkinson's disease. A few reports indicate that citicoline treatment may also be beneficial in glaucoma. Currently glaucoma is considered a neurodegenerative disease in which retinal ganglion cells (RGC) slowly die, likely in the apoptotic mechanism. Endogenous CDP-choline is a natural precursor of cellular synthesis of phospholipids, mainly phosphatydylcholine (PtdCho). Enhancement of PtdCho synthesis may counteract neuronal apoptosis and provide neuroprotection. Citicoline, when administered, undergoes a quick transformation to cytidine and choline, which are believed to enter brain cells separately and provide neuroprotection by enhancing PtdCho synthesis; similar effect may be expected to occur in glaucomatous RGC. Furthermore, citicoline stimulates some brain neurotransmitter systems, including the dopaminergic system, and dopamine is known as a major neurotransmitter in retina and postretinal visual pathways. In a double-blind, placebo-controlled study, treatment of glaucoma resulted in functional improvement in the visual system noted with electrophysiological methods. Development of citicoline as a treatment for glaucoma is indicated.     

Central NUCB2/Nesfatin‐1‐Expressing Neurones Belong to the Hypothalamic‐Brainstem Circuitry Activated by Hypoglycaemia

Nesfatin‐1 is a recently identified 82 amino acid peptide shown to have an anorexigenic effect on rodents when administrered centrally and peripherally. Nesfatin‐1 is expressed not only in neurones of various brain areas, including the hypothalamic and brainstem nuclei, but also in peripheral organs, such as the stomach and the pancreas. Nesfatinergic neurones were reported to participate in the regulation of satiety signals and in the responses to other stimuli, including restraint stress, abdominal surgery, and lipopolysaccharide‐induced inflammation. The present study aimed to investigate whether NUCB2/nesfatin‐1 expressing neurones also take part in the central signalling activated in response to hypoglycaemia and therefore are involved in central glucose sensing. Using immunolabelling methods based on the detection of the neuronal activation marker c‐Fos and of nesfatin‐1, we showed that peripheral injection of insulin induced a strong activation of nesfatin‐1‐expressing neurones in the brain vagal‐regulatory nuclei, including the arcuate nucleus, paraventricular nucleus, lateral hypothalamic area, dorsal motor nucleus of the vagus (DMNX) and nucleus of the tractus solitarius. In response to intracellular glucopaenia induced by i.p. or i.c.v. 2‐deoxyglucose injection, the c‐Fos/nesfatin‐1 colocalisations observed at the hypothalamic and brainstem levels were similar to those observed after insulin‐induced hypoglycaemia. Moreover, using Fluorogold as a retrograde tracer, we showed that nesfatinergic preganglionic DMNX neurones activated by hypoglycaemia target the stomach and the pancreas. Taken together, these results suggest that a subpopulation of nesfatinergic neurones belongs to the central network activated by hypoglycaemia, and that nesfatin‐1 participates in the triggering of physiological and hormonal counter‐regulations observed in response to hypoglycaemia.     

Insulin‐induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice

Stress suppresses pulsatile luteinising hormone (LH) secretion in a variety of species, although the mechanism underlying this inhibition of reproductive function remains unclear. Metabolic stress, particularly hypoglycaemia, is a clinically‐relevant stress type that is modelled with bolus insulin injection (insulin‐induced hypoglycaemia). The present study utilised ovariectomised C57BL/6 mice to test the hypothesis that acute hypoglycaemia suppresses pulsatile LH secretion via central mechanisms. Pulsatile LH secretion was measured in 90‐minute sampling periods immediately prior to and following i.p. injection of saline or insulin. The secretion of LH was not altered over time in fed animals or acutely fasted (5 hours) animals following an i.p. saline injection. By contrast, insulin elicited a robust suppression of pulsatile LH secretion in fasted animals, preventing LH pulses in five of six mice. To identify the neuroendocrine site of impairment, a kisspeptin challenge was performed in saline or insulin pre‐treated animals in a cross‐over design. LH secretion in response to exogenous kisspeptin was not different between animals pre‐treated with saline or insulin, indicating normal gonadotrophin‐releasing hormone cell and pituitary responses during acute hypoglycaemia. Based on this finding, the effect of insulin‐induced hypoglycaemia on arcuate kisspeptin (Kiss1) cell function was determined using c‐Fos as a marker of neuronal activation. Insulin caused a significant suppression in the percentage of Kiss1 cells in the arcuate nucleus that contained c‐Fos compared to saline‐injected controls. Taken together, these data support the hypothesis that insulin‐induced hypoglycaemia suppresses pulsatile LH secretion in the female mouse via predominantly central mechanisms, which culminates in the suppression of the arcuate Kiss1 population.     

Mineralocorticoid Receptor Activation Induces Insulin Resistance Through c‐Jun N‐terminal kinases in Response to Chronic Corticosterone: Cognitive Implications

It is becoming evident that chronic exposure to glucocorticoids might not only result in insulin resistance or cognitive deficits, but also is considered as a risk factor for pathologies such as depression or Alzheimer's disease. In the present study, in vivo experiments using a non‐invasive method of chronic administration of corticosterone in drinking water demonstrated that chronic corticosterone administration led to cognitive impairment in the novel object recognition test and insulin resistance, as shown by significant increases in plasma insulin levels and the homeostatic model assessment index, and decreased insulin receptor phosphorylation. Corticosterone treatment induced an increased expression of stress‐activated c‐Jun N‐terminal kinase (JNK) in the hippocampus, accompanied by decreases in glycogen synthase kinase 3β, increases in pTau levels and increased neuronal cell death (caspase‐3 activity). All these effects were reversed by the administration of a JNK1 inhibitor or by the mineralocorticoid receptor antagonist spironolactone. It is suggested that the mineralocorticoid receptors and JNK‐mediated pathways are involved in the interaction of glucocorticoid‐insulin resistance and the development of relevant cellular processes for Alzheimer′s disease     

Citicoline mechanisms and clinical efficacy in cerebral ischemia

Citicoline, an intermediate in the biosynthesis of phosphatidylcholine (PtdCho), has shown beneficial effects in various CNS injury models and neurodegenerative diseases. PtdCho hydrolysis by phospholipase A(2) (PLA(2)) after cerebral ischemia and reperfusion yields arachidonic acid (ArAc) and lyso-PtdCho. ArAc oxidative metabolism results in formation of reactive oxygen species and lipid peroxides. Lyso-PtdCho could inhibit activity of cytidine triphosphate-phosphocholine cytidylyltransferase (the rate-limiting enzyme in PtdCho biosynthesis), resulting in impaired PtdCho synthesis. Citicoline significantly increased glutathione levels and attenuated release of ArAc and the loss of PtdCho, cardiolipin, and sphingomyelin following transient cerebral ischemia. These effects could be explained by an effect of citicoline on PLA(2). Based on these observations, a mechanism has been hypothesized. This Mini-Review summarizes recent experimental data on the effects of citicoline in cerebral ischemia and evaluates several factors that might have hindered efficacy of citicoline in stroke clinical trials in the United States. Clinical stroke trials of citicoline in Europe and Japan have demonstrated beneficial effects. U.S. trials shown only marginal effects, which might be due to the 24 hr time window, the dose and route of administration, and the stringency of the primary outcome parameters. Recent evaluation of U.S. clinical data suggests that reduction of infarct growth may be a more sensitive measure of the citicoline effect than improvement on the NIH Stroke Scale (NIHSS) by > or =7 points. The citicoline neuroprotective mechanism has not been clearly identified, and its potential in stroke treatment might still be fully recognized in the United States. The clinical efficacy of citicoline should be examined further in light of the recent phase III stroke clinical trials and experimental data for cerebral ischemia.     

Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK‐3β and CREB through PI3‐K/Akt pathways

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK‐3β) and cAMP response element‐binding protein (CREB) through phosphatidylinositol 3‐kinase (PI3‐K)‐dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four‐vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK‐3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3‐K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK‐3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3‐K, compromised the neuroprotective effect of resveratrol and decreased the level of p‐Akt, p‐GSK‐3β and p‐CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro‐survival states of Akt, GSK‐3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3‐K/Akt signaling pathway, subsequently downregulating expression of GSK‐3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats.     

Autophagy impairment by caspase‐1‐dependent inflammation mediates memory loss in response to β‐Amyloid peptide accumulation

β‐Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by β‐Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, β‐Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the β‐Amyloid peptides impairs memory via disrupting the autophagic flux. We show that male mice overexpressing β‐Amyloid peptides (5XFAD) but lacking caspase‐1, presented reduced β‐Amyloid plaques in the cortex and in the hippocampus; restored brain autophagic flux and improved learning and memory capacity. At the molecular level, inhibition of the inflammatory response in the 5XFAD mice restored LC3‐II levels and prevented the accumulation of oligomeric p62 and ubiquitylated proteins. Furthermore, caspase‐1 deficiency reinstates activation of the AMPK/Raptor pathway while down‐regulating AKT/mTOR pathway. Consistent with this, we found an inverse correlation between the increase of autophagolysosomes in the cortex of 5XFAD mice lacking caspase‐1 and the presence of mitochondria with altered morphology. Together our results indicate that β‐Amyloid peptide‐induced caspase‐1 activation, disrupts autophagy in the cortex and in the hippocampus resulting in neurodegeneration and memory loss.     

Protective effects of peroxisome proliferator‐activated receptors γ coactivator‐1α against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia

Peroxisome proliferator‐activated receptors γ coactivator‐1α (PGC‐1α) may regulate the mitochondrial antioxidant defense system under many neuropathological settings. However, the exact role of PGC‐1α in ischemic brain damage is still under debate. Based on an experimental model of transient global ischemia (TGI), this study evaluated the hypothesis that the activation of PGC‐1α signaling pathway protects hippocampal CA1 neurons against delayed neuronal death after TGI. In Sprague‐Dawley rats, significantly increased content of oxidized proteins in the hippocampal CA1 tissue was observed as early as 30 min after TGI, followed by augmentation of PGC‐1α expression at 1 hr. Expression of uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2) in the hippocampal CA1 neurons was upregulated 4–48 hr after TGI. In addition, knock‐down of PGC‐1α expression by pretreatment with a specific antisense oligodeoxynucleotide in the hippocampal CA1 subfield downregulated the expression of UCP2 and SOD2 with resultant exacerbation of oxidative stress and augmentation of delayed neuronal cell death in the hippocampus after TGI. Overall, our results indicate that PGC‐1α is induced by cerebral ischemia leading to upregulation of UCP2 and SOD2, thereby providing a neuroprotective effect against ischemic brain injury in the hippocampus by ameliorating oxidative stress. © 2009 Wiley‐Liss, Inc.     

Use of catechol‐O‐methyltransferase inhibition to minimize L‐3,4‐dihydroxyphenylalanine‐induced dyskinesia in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐lesioned macaque

L‐3,4‐dihydroxyphenylalanine (L‐DOPA)‐induced dyskinesia is a complication of dopaminergic treatment in Parkinson's disease. Lowering the L‐DOPA dose reduces dyskinesia but also reduces the antiparkinsonian benefit. A therapy that could enhance the antiparkinsonian action of low‐dose L‐DOPA (LDl) without exacerbating dyskinesia would thus be of considerable therapeutic benefit. This study assessed whether catechol‐O‐methyltransferase (COMT) inhibition, as an add‐on to LDl, might be a means to achieve this goal. Cynomolgus macaques were administered 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine. Dyskinesia was established by chronic treatment with L‐DOPA. Two doses of L‐DOPA were identified – high‐dose L‐DOPA (LDh), which provided good antiparkinsonian benefit but was compromised by disabling dyskinesia, and LDl, which was sub‐threshold for providing significant antiparkinsonian benefit, without dyskinesia. LDh and LDl were administered in acute challenges in combination with vehicle and, for LDl, with the COMT inhibitor entacapone (5, 15 and 45 mg/kg). The duration of antiparkinsonian benefit (ON‐time), parkinsonism and dyskinesia were determined. The ON‐time after LDh was ～170 min and the ON‐time after LDl alone (～98 min) was not significantly different to vehicle (～37 min). In combination with LDl, entacapone significantly increased the ON‐time (5, 15 and 45 mg/kg being ～123, ～148 and ～180 min, respectively). The ON‐time after LDl/entacapone 45 mg/kg was not different to that after LDh. However, whereas the percentage ON‐time that was compromised by disabling dyskinesia was ～56% with LDh, it was only ～31% with LDl/entacapone 45 mg/kg. In addition to the well‐recognized action of COMT inhibition to reduce wearing‐OFF, the data presented suggest that COMT inhibition in combination with low doses of L‐DOPA has potential as a strategy to alleviate dyskinesia.     

Acute administration of the small‐molecule p75NTR ligand does not prevent hippocampal neuron loss or development of spontaneous seizures after pilocarpine‐induced status epilepticus

Neurotrophins, such as brain‐derived neurotrophic factor (BDNF), are initially expressed in a precursor form (e.g., pro‐BDNF) and cleaved to form mature BDNF (mBDNF). After pilocarpine‐induced status epilepticus (SE), increases in neurotrophins regulate a wide variety of cell‐signaling pathways, including prosurvival and cell‐death machinery in a receptor‐specific manner. Pro‐BDNF preferentially binds to the p75 neurotrophin receptor (p75^NTR), whereas mBDNF is the major ligand of the tropomyosin‐related kinase receptor. To elucidate a potential role for p75^NTR in acute stages of epileptogenesis, rats were injected prior to and at onset of SE with LM11A‐31, a small‐molecule ligand that binds to p75^NTR to promote survival signaling and inhibit neuronal cell death. Modulation of early p75^NTR signaling and its effects on electrographic SE, SE‐induced neurodegeneration, and subsequent spontaneous seizures were examined after LM11A‐31 administration. Despite an established neuroprotective effect of LM11A‐31 in several animal models of neurodegenerative disorders (e.g., Alzheimer's disease, traumatic brain injury, and spinal cord injury), high‐dose LM11A‐31 administration prior to and at onset of SE did not reduce the intensity of electrographic SE, prevent SE‐induced neuronal cell injury, or inhibit the progression of epileptogenesis. Further studies are required to understand the role of p75^NTR activation during epileptogenesis and in seizure‐induced cell injury in the hippocampus, among other potential cellular pathologies contributing to the onset of spontaneous seizures. Additional studies utilizing more prolonged treatment with LM11A‐31 are required to reach a definite conclusion on its potential neuroprotective role in epilepsy. © 2014 Wiley Periodicals, Inc.     

A DAP12‐Dependent signal promotes pro‐inflammatory polarization in microglia following nerve injury and exacerbates degeneration of injured neurons

Under pathological conditions, activated microglia play paradoxical roles and could have neurotoxic or neuroprotective effects. However, the signal determining how activated microglia affects the fate of neuronal cells remains largely unknown. Here we demonstrate that DNAX‐activating protein of 12 kDa (DAP12), a transmembrane adaptor protein that contains an immunoreceptor tyrosine‐based activation motif, is a critical regulator of microglial function after nerve injury. In a model of mouse hypoglossal nerve injury, the duration of microglial increase after nerve injury became shorter in mice lacking DAP12, although microglial morphology and total cell numbers were not significantly affected during early phase after nerve injury. Intriguingly, expressions of M1‐phenotype markers including pro‐inflammatory cytokines were suppressed in DAP12‐deficient microglia. Furthermore, axotomy‐induced motor neuron death was markedly prevented in DAP12‐deficient mice. Collectively, DAP12‐mediated microglial activation following axotomy promotes pro‐inflammatory responses, and thereby accelerates nerve injury‐induced neuron death, suggesting that DAP12 is a potential therapeutic target for the protection of neuronal degeneration caused by microglial activation. GLIA 2015;63:1073–1082     

The phosphodiesterase type 2 inhibitor BAY 60‐7550 reverses functional impairments induced by brain ischemia by decreasing hippocampal neurodegeneration and enhancing hippocampal neuronal plasticity

Cognitive and affective impairments are the most characterized consequences following cerebral ischemia. BAY 60‐7550, a selective phosphodiesterase type 2 inhibitor (PDE2‐I), presents memory‐enhancing and anxiolytic‐like properties. The behavioral effects of BAY 60‐7550 have been associated with its ability to prevent hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) thereby interfering with neuronal plasticity. Here, we hypothesize that PDE2‐I treatment could promote functional recovery after brain ischemia. Mice C57Bl/6 were submitted to bilateral common carotid artery occlusion (BCCAO), an experimental model of transient brain ischemia, for 20 min. During 21 days after reperfusion, the animals were tested in a battery of behavioral tests including the elevated zero maze (EZM), object location task (OLT) and forced swim test (FST). The effects of BAY 60‐7550 were evaluated on neuronal nuclei (NeuN), caspase‐9, cAMP response element‐binding protein (CREB), phosphorylated CREB (pCREB) and brain‐derived neurotrophic factor (BDNF) expression in the hippocampus. BCCAO increased anxiety levels, impaired hippocampus‐dependent cognitive function and induced despair‐like behavior in mice. Hippocampal neurodegeneration was evidenced by a decrease in NeuN and increase incaspase‐9 protein levels in BCCAO mice. Ischemic mice also showed low BDNF protein levels in the hippocampus. Repeated treatment with BAY 60‐7550 attenuated the behavioral impairments induced by BCCAO in mice. Concomitantly, BAY 60‐7550 enhanced expression of pCREB and BDNF protein levels in the hippocampus of ischemic mice. The present findings suggest that chronic inhibition of PDE2 provides functional recovery in BCCAO mice possibly by augmenting hippocampal neuronal plasticity.     

Blocking brain‐derived neurotrophic factor inhibits injury‐induced hyperexcitability of hippocampal CA3 neurons

Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin‐related kinase B (TrkB), a receptor for brain‐derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF‐mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury‐induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB‐Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB‐Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two‐fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB‐Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB‐Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury‐induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post‐traumatic epilepsy. Therefore, our data suggest that blocking the BDNF–TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post‐traumatic epilepsy.