Neuroprotection of donepezil against morphine-induced apoptosis is mediated through Toll-like receptors

Shafie, Alireza; Moradi, Farshid; Izadpanah, Esmael; Mokarizadeh, Aram; Moloudi, Mohammad Raman; Nikzaban, Mehrnoush; Hassanzadeh, Kambiz

doi:10.1016/j.ejphar.2015.07.027

Cited by 20 publications

(12 citation statements)

References 34 publications

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“…Studies demonstrated that systemic antagonism of TLR4 improved morphine tolerance. Inhibition of TLR4 gene expression [ 40 ] or blockade of TLR4 downstream signals both led to a marked potentiation of the magnitude and duration of opioid analgesia [ 41 ]. Unfortunately, there is no safe and effective TLR4 inhibitor available in clinic for the treatment of morphine tolerance.…”

Section: Discussionmentioning

confidence: 99%

Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

Zhang

Tao

et al. 2017

J Neuroinflammation

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BackgroundMorphine tolerance is a clinical challenge, and its pathogenesis is closely related to the neuroinflammation mediated by Toll-like receptor 4 (TLR4). In Chinese pain clinic, lidocaine is combined with morphine to treat chronic pain. We found that lidocaine sufficiently inhibited neuroinflammation induced by morphine and improved analgesic tolerance on the basis of non-affecting pain threshold.MethodsCD-1 mice were utilized for tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of lidocaine. Neuroinflammation-related cytokines were measured by western blotting and real-time PCR. The level of suppressor of cytokine signaling 3 (SOCS3) and adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK)-related signaling pathway was evaluated by western blotting, real-time PCR, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence staining.ResultsLidocaine potentiated an anti-nociceptive effect of morphine and attenuated the chronic analgesic tolerance. Lidocaine suppressed morphine-induced activation of microglia and downregulated inflammatory cytokines, interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) via upregulating SOCS3 by activating AMPK. Lidocaine enhanced AMPK phosphorylation in a calcium-dependent protein kinase kinase β (CaMKKβ)-dependent manner. Furthermore, lidocaine decreased the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and inhibited the nuclear factor-κB (NF-κB) in accordance with the inhibitory effects to TLR4.ConclusionsLidocaine as a prevalent local anesthetic suppresses morphine tolerance efficiently. AMPK-dependent upregulation of SOCS3 by lidocaine plays a crucial role in the improvement of analgesic tolerance.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0983-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

Zhang

Tao

et al. 2017

J Neuroinflammation

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“…Previous studies have indicated that donepezil generates beneficial effects in neuronal damage and cognitive deficits after ischemic insults 4 5 . Donepezil also displays anti-apoptotic effects against morphine-induced apoptosis in rat cerebral cortex and lumbar spinal cord 6 7 . Those data imply that donepezil can exert its action on multiple targets.…”

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confidence: 99%

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

Neng

2017

Sci Rep

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Kv1.5 channels carry ultra-rapid delayed rectifier K+ currents in excitable cells, including neurons and cardiac myocytes. In the current study, the effects of cholinesterase inhibitor donepezil on cloned Kv1.5 channels expressed in HEK29 cells were explored using whole-cell recording technique. Exposure to donepezil resulted in a rapid and reversible block of Kv1.5 currents, with an IC50 value of 72.5 μM. The mutant R476V significantly reduced the binding affinity of donepezil to Kv1.5 channels, showing the target site in the outer mouth region. Donepezil produced a significant delay in the duration of activation and deactivation, and mutant R476V potentiated these effects without altering activation curves. In response to slowed deactivation time course, a typical crossover of Kv1.5 tail currents was clearly evident after bath application of donepezil. In addition, both this chemical and mutant R476V accelerated current decay during channel inactivation in a voltage-dependent way, but barely changed the inactivation and recovery curves. The presence of donepezil exhibited the use-dependent block of Kv1.5 currents in response to a series of depolarizing pulses. Our data indicate that donepezil can directly block Kv1.5 channels in its open and closed states.

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“…There were many researchers [6,7] who have reported that morphine could induce apoptosis of neurons. There were many other research studies [8,9] which have reported that downregulation or antagonist of the CCK receptor promotes apoptosis, which indicates that CCK may inhibit apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Effect of CCK-8 on the Expression of Bax, Bcl-2 and Caspase-3 of the Hippocampus CA1 Neurons in Morphine in Relapsed Rats

Ye¹,

Ma²,

Gao³

et al. 2018

Clin Diagn Pathol

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Objective: To explore the neuroprotective mechanisms of CCK-8 for morphine relapse by researching the effect of CCK-8 on the expression of Bax, Bcl-2 and Caspase-3 of hippocampus CA1 neurons in morphine-relapsed rats.Methods: A total of 40 healthy male Wistar rats (weight 200g ± 10g) were divided into the following groups: normal saline (NS) group (n=8); morphine (MOR) group (n=8); and CCK-8 treated group (n=24). The groups were selected by the random peer-to-peer principle. The CCK-8 treated group was subdivided into 0.01μg CCK-8 group (n=8), 0.1 μg CCK-8 group (n=8) and 1.0 μg CCK-8 group (n=8). First we established the models of morphine-relapsed rats under CCK-8 intervention using the Conditioned Place Preference (CPP) methods. Three different doses of CCK-8 (0.01, 0.1 and 1.0 μg, i.c.v) were injected 15 minutes before morphine administration during the conditioning phase. All rats were decapitated and their hippocampi CA1 were made into slices with immunohistochemical stains. The expressions of Bax, Bcl-2, Caspase-3 of neurons were then measured by their ODs, and each ratio of Bax and Bcl-2 (Bax/Bcl-2) were calculated using a microscope connected to a computer equipped with Image-ProPlus software.Results: In the NS group, the expression of Bcl-2 was very weak and the expression of Bax and Caspase-3 was barely observed. In the MOR group, the expression of Bax and Caspase-3 was strong and that of Bcl-2 was weak, and there were significant differences (P<0.05) compared to the NS group. As to Bax, Caspase-3 the ratio of Bax/ Bcl-2, showed a gradually decreasing trend in the sequence of group 0.01 μg, group 0.1 μg, and group 1.0 μg, but when it came to that of Bcl-2, it was opposite. There were significant differences (P<0.05), compared to the MOR group, except in group 0.01 μg. Conclusion:CCK-8 could up regulate the expression of Bcl-2, down regulate Bax and Caspase-3 as well as reduce the Bax/ Bcl-2 ratio of neurons of hippocampus CA1 in the model of morphine-relapsed rats. This may be one of the main neuroprotective mechanisms of CCK-8 for morphine relapse.

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Neuroprotection of donepezil against morphine-induced apoptosis is mediated through Toll-like receptors

Cited by 20 publications

References 34 publications

Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

Lidocaine alleviates morphine tolerance via AMPK-SOCS3-dependent neuroinflammation suppression in the spinal cord

Inhibitory effects of cholinesterase inhibitor donepezil on the Kv1.5 potassium channel

Effect of CCK-8 on the Expression of Bax, Bcl-2 and Caspase-3 of the Hippocampus CA1 Neurons in Morphine in Relapsed Rats

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