Antidepressant drugs in convulsive seizures: Pre-clinical evaluation of duloxetine in mice

Santana‐Coelho, Danielle; Souza-Monteiro, José Rogerio; Paraense, Ricardo S.O.; Busanello, Guilherme L.; Arrifano, Gabriela de Paula; Mendonça, Jackson R.; Silveira-Junior, Mauro E.P.; Royes, Luiz Fernando Freire; Crespo-López, María Elena

doi:10.1016/j.neuint.2016.06.001

Cited by 13 publications

(7 citation statements)

References 72 publications

(2 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neuronal injury is followed by microglial cell activation [24]. PTZ was reported to induce astrogliosis [4,50,65].…”

Section: Controlmentioning

confidence: 99%

Neuroprotective effect of nilotinib on pentylenetetrazol-induced epilepsy in adult rat hippocampus: involvement of oxidative stress, autophagy, inflammation, and apoptosis

Attia¹,

Elmansy²,

Elsaed³

2019

View full text Add to dashboard Cite

Introduction: Neuronal cell death and glial cell activation are the main pathological findings induced by seizures secondary to oxidative stress. Previous studies have explained neuronal cell death on the basis of cell necrosis and apoptosis. Recent studies have attributed the neuronal loss to autophagy. The proved antioxidant and antifibrotic effect of nilotinib favours its use in the management of epileptic seizures. Aim of the study was to analyse the neuroprotective and antiepileptic effect of nilotinib and explain its mechanism of action. Material and methods: Forty adult male rats were divided into four groups: control, pentylenetetrazol (PTZ) group (injected with PTZ 60 mg/kg, s.c.), pregabalin (Pregb)-PTZ group (pretreated with pregabalin daily 30 mg/kg; orally for 1 week) and nilotinib (NIL)-PTZ group (pretreated with nilotinib, 25 mg/kg daily for 1 week) prior to PTZ. Seizure latency was evaluated, the hippocampus tissue level of antioxidant enzymes was assessed. The histopathological changes in the hippocampus were studied using hematoxylin and eosin stain and immunohistochemical stain for brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), beclin-1, nuclear factor kappa-B (NF-κB) and Bcl-2-like protein 4 (BAX). Results: Nilotinib induced an increase in the latency of seizures, enhanced the antioxidant levels of the γ-aminobutyric acid and nuclear factor (erythroid-derived 2)-like 2 activities together with the improvement of the hippocampal histology. A reduction was reported for BDNF, GFAP, beclin-1, NF-κB and BAX expression in nerve cells. Conclusions: Nilotinib may have promising neuroprotective and antiepileptic effects against pentylenetetrazolinduced seizures through promoting the antioxidant, antifibrotic, anti-inflammatory, antiapoptotic pathways and inhibiting autophagy.

show abstract

“…Neuronal injury is followed by microglial cell activation [24]. PTZ was reported to induce astrogliosis [4,50,65].…”

Section: Controlmentioning

confidence: 99%

Neuroprotective effect of nilotinib on pentylenetetrazol-induced epilepsy in adult rat hippocampus: involvement of oxidative stress, autophagy, inflammation, and apoptosis

Attia¹,

Elmansy²,

Elsaed³

2019

View full text Add to dashboard Cite

show abstract

“…Of note, based on these data and the fact that 35 µM of duloxetine has the capacity to exert significant inhibitory effects on platelet function regardless of the platelet function assay and/or agonist used, this dose was selected for further in vitro experimentation. Following this, we examined its ex vivo effects by injecting mice with 20 mg/kg of duloxetine, which was selected based on a literature review [ 16 , 17 , 18 , 19 , 20 , 21 ], before platelets were collected and their aggregation response examined. Indeed, duloxetine significantly reduced ADP- (58% ± 13), and U46619 (43% ± 11)-induced platelet aggregation ( Figure 1 C,D, respectively).…”

Section: Resultsmentioning

confidence: 99%

“…In order to address this issue, we examined whether duloxetine modulates thrombogenesis and hemostasis in live mice. We used a dose (20 mg/kg) that corresponds to the therapeutic range for MDD treatment in humans [ 17 , 42 ]. It was observed that duloxetine-treated mice present a prolonged occlusion time in comparison with the vehicle-treated mice.…”

Section: Discussionmentioning

confidence: 99%

The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis

Lozano

Alarabi

Garcia

et al. 2022

IJMS

View full text Add to dashboard Cite

While cardiovascular disease (CVD) is the leading cause of death, major depressive disorder (MDD) is the primary cause of disability, affecting more than 300 million people worldwide. Interestingly, there is evidence that CVD is more prevalent in people with MDD. It is well established that neurotransmitters, namely serotonin and norepinephrine, are involved in the biochemical mechanisms of MDD, and consequently, drugs targeting serotonin-norepinephrine reuptake, such as duloxetine, are commonly prescribed for MDD. In this connection, serotonin and norepinephrine are also known to play critical roles in primary hemostasis. Based on these considerations, we investigated if duloxetine can be repurposed as an antiplatelet medication. Our results-using human and/or mouse platelets show that duloxetine dose-dependently inhibited agonist-induced platelet aggregation, compared to the vehicle control. Furthermore, it also blocked agonist-induced dense and α-granule secretion, integrin αIIbβ3 activation, phosphatidylserine expression, and clot retraction. Moreover duloxetine-treated mice had a significantly prolonged occlusion time. Finally, duloxetine was also found to impair hemostasis. Collectively, our data indicate that the antidepressant duloxetine, which is a serotonin-norepinephrine antagonist, exerts antiplatelet and thromboprotective effects and inhibits hemostasis. Consequently, duloxetine, or a rationally designed derivative, presents potential benefits in the context of CVD, including that associated with MDD.

show abstract

“…Pentylenetetrazol is a central nervous system stimulant and so it is used to study experimentally induced seizures and to compare newly marketed antiepileptic drugs [41]. [56][57][58]. The cerebral cortex is mainly sensitive to hypoxic states evoked by severe brain activity as occurs in status epilepticus (SE) [59,60].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Nilotinib on Cortical Pyramidal Cells, Histological, Morphometric and Biochemical Study

Ahmed

2020

ARRB

View full text Add to dashboard Cite

Introduction: Death of neuronal cell and gliosis are the two main pathological hallmarks induced by nervous tissue stress like conditions such as status epilepticus. Previous studies have mentioned that neuronal cell death occur as a result of different mechanisms, namely, necrosis and apoptosis. Although more recent studies have explained the cell death on the basis of autophagy. Many antiepileptic drugs are marketed, taking into consideration the antioxidant role of nilotinib and support its use as a favorable antiepileptic drug. The aim of the present study is to assess the neuroprotective effect of antiepileptic drug nilotinib on cortical tissue in rats. Materials and Methods: Sixty adult male rats were divided into three groups: (1) Control group, (2) pentylenetetrazol group (injected with pentylenetetrazol 60 mg/kg, subcutaneously), (3) nilotinib and pentylenetetrazol group (pretreated with nilotinib, 25 mg/kg daily for seven days prior to pentylenetetrazol administration). Latency of seizure and level of either oxidant or antioxidant enzymes in the cortical tissue was assessed. The histopathological changes in the cerebral cortex were studied also using hematoxylin and eosin stain. Results: Nilotinib increased the latency period of convulsions, increased the antioxidant enzymes levels with regain of the normal histological features. Conclusions: Nilotinib proved to promote the antioxidant, antiapoptotic pathways, anti-inflammatory and inhibiting autophagy which favor its use as an anti-epileptic drug.

show abstract

Antidepressant drugs in convulsive seizures: Pre-clinical evaluation of duloxetine in mice

Cited by 13 publications

References 72 publications

Neuroprotective effect of nilotinib on pentylenetetrazol-induced epilepsy in adult rat hippocampus: involvement of oxidative stress, autophagy, inflammation, and apoptosis

Neuroprotective effect of nilotinib on pentylenetetrazol-induced epilepsy in adult rat hippocampus: involvement of oxidative stress, autophagy, inflammation, and apoptosis

The Antidepressant Duloxetine Inhibits Platelet Function and Protects against Thrombosis

Neuroprotective Effect of Nilotinib on Cortical Pyramidal Cells, Histological, Morphometric and Biochemical Study

Contact Info

Product

Resources

About