Region-specific alterations of AMPA receptor phosphorylation and signaling pathways in the pilocarpine model of epilepsy

Lopes, Mark William; Lopes, Samantha Cristiane; Costa, Ana Paula; Gonçalves, Filipe Marques; Rieger, Débora Kurrle; Peres, Tanara Vieira; Eyng, Helena; Prediger, Rui Daniel; Diaz, Alexandre Paim; Nunes, Jean Costa; Walz, Roger; Leal, Rodrigo Bainy

doi:10.1016/j.neuint.2015.05.003

Cited by 35 publications

(26 citation statements)

References 60 publications

(81 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several selective AMPA receptor antagonists were demonstrated to have broad spectrum anticonvulsant activity in sound-induced seizures in rats and in amygdala-kindled rats [38,39]. Similarly, a decrease of phosphorylated AMPA glutamate receptor subunit (GluA1) was found in the dorsal hippocampus of rats after chronic pilocarpine treatment [40]. In addition, AMPA receptor antagonists were widely found to be safe and effective in patients with partial-onset seizures [41], raising a possibility that AMPA receptor can be a novel target for epilepsy therapy.…”

Section: Discussionmentioning

confidence: 99%

AMPA Receptor Antagonist NBQX Decreased Seizures by Normalization of Perineuronal Nets

Chen

Gao

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

Epilepsy is a serious brain disorder with diverse seizure types and epileptic syndromes. AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzoquinoxaline-2,3-dione (NBQX) attenuates spontaneous recurrent seizures in rats. However, the anti-epileptic effect of NBQX in chronic epilepsy model is poorly understood. Perineuronal nets (PNNs), specialized extracellular matrix structures, surround parvalbumin-positive inhibitory interneurons, and play a critical role in neuronal cell development and synaptic plasticity. Here, we focused on the potential involvement of PNNs in the treatment of epilepsy by NBQX. Rats were intraperitoneally (i.p.) injected with pentylenetetrazole (PTZ, 50 mg/kg) for 28 consecutive days to establish chronic epilepsy models. Subsequently, NBQX (20 mg/kg, i.p.) was injected for 3 days for the observation of behavioral measurements of epilepsy. The Wisteria floribundi agglutinin (WFA)-labeled PNNs were measured by immunohistochemical staining to evaluate the PNNs. The levels of three components of PNNs such as tenascin-R, aggrecan and neurocan were assayed by Western blot assay. The results showed that there are reduction of PNNs and decrease of tenascin-R, aggrecan and neurocan in the medial prefrontal cortex (mPFC) in the rats injected with PTZ. However, NBQX treatment normalized PNNs, tenascin-R, aggrecan and neurocan levels. NBQX was sufficient to decrease seizures through increasing the latency to seizures, decrease the duration of seizure onset, and reduce the scores for the severity of seizures. Furthermore, the degradation of mPFC PNNs by chondroitinase ABC (ChABC) exacerbated seizures in PTZ-treated rats. Finally, the anti-epileptic effect of NBQX was reversed by pretreatment with ChABC into mPFC. These findings revealed that PNNs degradation in mPFC is involved in the pathophysiology of epilepsy and enhancement of PNNs may be effective for the treatment of epilepsy.

show abstract

Section: Discussionmentioning

confidence: 99%

AMPA Receptor Antagonist NBQX Decreased Seizures by Normalization of Perineuronal Nets

Chen

Gao

et al. 2016

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…), and altered neurotransmitter receptor composition (Lopes et al . ; Zhou et al . ) at remaining synapses.…”

Section: Synapse Dysfunction In Neurodevelopmental Disordersmentioning

confidence: 99%

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Lepeta

Lourenco

Schweitzer

et al. 2016

Journal of Neurochemistry

296

220

View full text Add to dashboard Cite

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in diseaseassociated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders.

show abstract

“…To quantify CREB phosphorylation and immunocontent, western blotting analysis was performed as previously described [47,54,55]. Animals were euthanized by decapitation; brains were excised from the skull; and hippocampi and prefrontal cortex were dissected into cold saline solution, placed in liquid nitrogen, and then stored at −80°C until use.…”

Section: Western Blottingmentioning

confidence: 99%

Signaling pathways underlying the antidepressant-like effect of inosine in mice

Gonçalves

Neis

Rieger

et al. 2016

Purinergic Signalling

Self Cite

View full text Add to dashboard Cite

Inosine is a purine nucleoside formed by the breakdown of adenosine that elicits an antidepressant-like effect in mice through activation of adenosine A 1 and A 2A receptors. However, the signaling pathways underlying this effect are largely unknown. To address this issue, the present study investigated the influence of extracellular-regulated protein kinase (ERK)1/2, Ca 2+ /calmoduline-dependent protein kinase (CaMKII), protein kinase A (PKA), phosphoinositide 3-kinase (PI3K)/Akt, and glycogen synthase kinase 3beta (GSK-3β) modulation in the antiimmobility effect of inosine in the tail suspension test (TST) in mice. In addition, we attempted to verify if inosine treatment was capable of altering the immunocontent and phosphorylation of the transcription factor cyclic adenosine monophosphatate (cAMP) responsebinding element protein (CREB) in mouse prefrontal cortex and hippocampus. Intracerebroventricular administration of U0126 (5 μg/mouse, MEK1/2 inhibitor), KN-62 (1 μg/ mouse, CaMKII inhibitor), H-89 (1 μg/mouse, PKA inhibitor), and wortmannin (0.1 μg/mouse, PI3K inhibitor) prevented the antiimmobility effect of inosine (10 mg/kg, intraperitoneal (i.p.)) in the TST. Also, administration of a subeffective dose of inosine (0.1 mg/kg, i.p.) in combination with a sub-effective dose of AR-A014418 (0.001 μg/mouse, GSK-3β inhibitor) induced a synergic antidepressant-like effect. None of the treatments altered locomotor activity of mice. Moreover, 24 h after a single administration of inosine (10 mg/kg, i.p.), CREB phosphorylation was increased in the hippocampus. Our findings provided new evidence that the antidepressant-like effect of inosine in the TST involves the activation of PKA, PI3K/Akt, ERK1/2, and CaMKII and the inhibition of GSK-3β. These results contribute to the comprehension of the mechanisms underlying the purinergic system modulation and indicate the intracellular signaling pathways involved in the antidepressant-like effect of inosine in a preclinical test of depression.

show abstract

Region-specific alterations of AMPA receptor phosphorylation and signaling pathways in the pilocarpine model of epilepsy

Cited by 35 publications

References 60 publications

AMPA Receptor Antagonist NBQX Decreased Seizures by Normalization of Perineuronal Nets

AMPA Receptor Antagonist NBQX Decreased Seizures by Normalization of Perineuronal Nets

Synaptopathies: synaptic dysfunction in neurological disorders – A review from students to students

Signaling pathways underlying the antidepressant-like effect of inosine in mice

Contact Info

Product

Resources

About