Exacerbated status epilepticus and acute cell loss, but no changes in epileptogenesis, in mice with increased brain-derived neurotrophic factor signaling

Lähteinen, Sari; Pitkänen, Asla; Koponen, Eija; Saarelainen, Tommi; Ċastrén, Eero

doi:10.1016/j.neuroscience.2003.08.037

Cited by 58 publications

(33 citation statements)

References 59 publications

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“…Intrahippocampal kainate administration leads to neuronal depolarization that, in turn, releases neurotrophins that will further depolarize neurons creating an excitatory feedback loop that may eventually lead to hyperexcitation. In fact, intrahippocampal application of BDNF elicits electrographic discharges with subsequent spontaneous seizures (18) and it can exacerbate an ongoing status epilepticus (19). Since secreted neurotrophins can powerfully stimulate protein tyrosine kinase receptors leading to phosphorylation of tyrosine residues (20), we speculate that K252a and herbimycin attenuate the electrographic seizures by decreasing tyrosine phosphorylation signaling.…”

Section: Discussionmentioning

confidence: 98%

Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

Queiroz

Mello

2008

Braz J Med Biol Res

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Intrahippocampal administration of kainic acid (KA) induces synaptic release of neurotrophins, mainly brain-derived neurotrophic factor, which contributes to the acute neuronal excitation produced by the toxin. Two protein tyrosine kinase inhibitors, herbimycin A and K252a, were administered intracerebroventricularly, in a single dose, to attenuate neurotrophin signaling during the acute effects of KA, and their role in epileptogenesis was evaluated in adult, male Wistar rats weighing 250-300 g. The latency for the first Racine stage V seizure was 90 ± 8 min in saline controls (N = 4) which increased to 369 ± 71 and 322 ± 63 min in animals receiving herbimycin A (1.74 nmol, N = 4) and K252a (10 pmol, N = 4), respectively. Behavioral alterations were accompanied by diminished duration of EEG paroxysms in herbimycin A-and K252a-treated animals. Notwithstanding the reduction in seizure severity, cell death (60-90% of cell loss in KA-treated animals) in limbic regions was unchanged by herbimycin A and K252a. However, aberrant mossy fiber sprouting was significantly reduced in the ipsilateral dorsal hippocampus of K252a-treated animals. In this model of temporal lobe epilepsy, both protein kinase inhibitors diminished the acute epileptic activity triggered by KA and the ensuing morphological alterations in the dentate gyrus without diminishing cell loss. Our current data indicating that K252a, but not herbimycin, has an influence over KA-induced mossy fiber sprouting further suggest that protein tyrosine kinase receptors are not the only factors which control this plasticity. Further experiments are necessary to elucidate the exact signaling systems associated with this K252a effect.

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Section: Discussionmentioning

confidence: 98%

Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

Queiroz

Mello

2008

Braz J Med Biol Res

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“…Also, there was a trend to a direct correlation between seizure frequency and TrkB expression. The close relationship of TrkB and epileptogenesis has been explored in animal models for more than a decade [17,19,22,23,69,70], and TrkB acts as an indispensable molecule for seizure generation and epilepsy development. Here we described for the first time in human MTLE that even in a chronic scenario TrkB may play a major role on seizure type and epilepsy surgery outcome.…”

Section: Discussionmentioning

confidence: 99%

Neurotrophin receptors expression in mesial temporal lobe epilepsy with and without psychiatric comorbidities and their relation with seizure type and surgical outcome

Kandratavicius

Hallak

Carlotti

et al. 2014

Acta Neuropathologica Communications

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Epilepsy and psychiatric comorbidities are frequently associated, but their common biological substrate is unknown. We have previously reported altered structural elements and neurotrophins (NTs) expression in mesial temporal lobe epilepsy (MTLE) patients with psychiatric comorbidities. NTs receptors can regulate neurotransmission and promote neuroplasticity, being important candidates in the regulation and manifestation of psychopatological states and seizure-related events. MTLE hippocampi of subjects without psychiatric history, MTLE + major depression, MTLE + interictal psychosis derived from epilepsy surgery, and control necropsies were investigated for p75 NTR , TrkB, TrkA, and TrkC immunohistochemistry. Increased expression of p75 NTR , decreased TrkA, unaltered TrkC, and complex alterations involving TrkB expression were seen in MTLE groups. Increased TrkB expression in patients without complete seizure remission and in those with secondarily generalized seizures was seen. Decreased p75 NTR expression associated with interictal psychosis, and increased TrkB in those with psychosis or major depression was also reported, although their p75 NTR /TrkB ratios were lower than in MTLE without psychiatric comorbidities. Our results provide evidence of alterations in expression of NTs receptors in the epileptogenic hippocampus that are differentially modulated in presence of psychiatric comorbidities. As already explored in animal models, even in chronic human MTLE increased TrkB expression, among other NT receptors alterations, may play a major role in seizure type, frequency and surgery outcome.

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“…In fact, an indiscriminate overload of BDNF in the brain might cause several problems related to neuronal excitability: to this end, it has been demonstrated that BDNF increases neuronal excitability and can exacerbate seizure development. 33 Similarly, Scharfman et al In an attempt to overcome such delivery problems, different methods have been developed, which, however, did not solve the problem. In fact, the possibility exists to supplement BDNF through engineered cells that overexpress BDNF or, alternatively, to use viral vectors in order to appropriately vehicolate the neurotrophin.…”

Section: Exogenous Administration Of Bdnf: Pros and Consmentioning

confidence: 99%

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

2005

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Finding an effective treatment for chronic neurodegenerative disorders still represents an unmet goal. There is considerable evidence that such disorders represent a combination of genetic determinants and failure of neuroprotective mechanisms sparking a wider degree of interest in shedding light on the cellular changes responsible for these devastating disorders. Because of their role in survival or differentiation of developing neurons, as well as the recent discovery of their importance in regulating synaptic plasticity during adulthood, neurotrophic factors have been suggested as essential contributors of the etiology of neurodegenerative disorders. Alzheimer's disease (AD) is a complex, chronic, devastating disease that affects a high percentage of the population over 65 years of age. This review will focus on different pharmacological interventions that are currently in use or drugs under development, narrowing the therapeutic agents to those that interfere with the expression of the trophic factor brain-derived neurotrophic factor (BDNF), a molecule playing a pivotal role in synaptic plasticity and cognition. From these findings, it appears clear that BDNF is implicated in the mechanism of action of drugs that improve cognitive deficits in animal models of AD and in AD patients.

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Exacerbated status epilepticus and acute cell loss, but no changes in epileptogenesis, in mice with increased brain-derived neurotrophic factor signaling

Cited by 58 publications

References 59 publications

Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

Protein tyrosine kinase inhibitors modify kainic acid-induced epileptiform activity and mossy fiber sprouting but do not protect against limbic cell death

Neurotrophin receptors expression in mesial temporal lobe epilepsy with and without psychiatric comorbidities and their relation with seizure type and surgical outcome

The expanding role of BDNF: a therapeutic target for Alzheimer's disease?

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