Properties of gap junction blockers and their behavioural, cognitive and electrophysiological effects: Animal and human studies

Juszczak, Grzegorz R.; Świergiel, Artur H.

doi:10.1016/j.pnpbp.2008.12.014

Cited by 191 publications

(170 citation statements)

References 305 publications

Supporting

Mentioning

163

Contrasting

Order By: Relevance

“…Thus, gap junctions have a confirmed role in pain sensation at the level of the spinal cord, as also inferred by our results. Astrocyte gap junctions can be involved in the release of important biomolecules such as ATP and glutamate, which in turn are involved in neuron-neuron, glial-glial and neuronglial cell interactions (6). Alongside our results this confirms the involvement of gap junctions in pain sensation modulation, and thus gap junction blockage probably has a pain alleviating effect as seen in the results of the present study for chemical pain sensation (Figure 3).…”

Section: Discussionsupporting

confidence: 90%

See 1 more Smart Citation

Effects of Intrathecal Carbenoxolone Treatment on Nociception and Analgesia in Rat

Kamalpour¹,

Fereidoni²,

Moghimi³

2014

Balkan Med J

View full text Add to dashboard Cite

Background: Gap junctions (GJ) are important in pain signalling at the spinal cord level. Aims: The aim of this investigation was to study the effects of GJ on nociception and the analgesic/hyperalgesic effects of mor phine following administration of carbenoxolone as a GJ blocker. Male Wistar rats (200-250 g) were divided into three groups: saline i.p., 10 mg/kg and 1 μg/kg i.p. morphine, each with two subgroups. One was treated intrathecally with saline and the other with carben oxolone. Study Design: Animal experiment. Methods: The thermal nociception threshold was measured prior to and after injections using the tail flick test. Chemical nociception assessment was conducted using a 0.05-mL subplantar injection of 2.5% formalin. Results: Both formalin-induced neurogenic and inflammatory nociception were reduced in the [saline i.p./carbenoxolone i.t.] and [morphine 1 µg/kg, i.p./carbenoxolone i.t.] subgroups (p<0.001). The 10 mg/kg i.p. morphine, i.t./carbenoxolone treatment reduced morphineinduced analgesia in the inflammatory phase (p<0.05), while it was ineffective in the neurogenic phase. Carbenoxolone decreased 1 µg/ kg i.p. morphine-induced hyperalgesia in the tail flick test (p<0.001). Conclusion: Based on the results, GJ probably play a role in nociception at the spinal cord level. This may be due to the facilitation of inflammatory mediators released from glial cells or the connection between stimulatory interneurons and projection neurons. GJ blocking attenuated morphine-induced analgesia. This may be due to the attenuation of pre/post-synaptic inhibitory effects of morphine at the spinal cord level. As demonstrated by the investigations, GJ are present between inhibitory interneurons. Therefore, we can assume that blockage of GJ between inhibitory interneurons will reduce morphine-induced analgesia at the spinal cord level. However, this requires further investigation. (Balkan Med J 2014;31:164-72).

show abstract

Section: Discussionsupporting

confidence: 90%

“…Gap junctions play an important role in the central nervous system (CNS). They synchronize neuronal activities and join up the glial cells, which regulate the homeostasis and metabolism of the brain and spinal cord (6). The presence of gap junctions between the neurons was first confirmed using electrophysiological recording methods.…”

mentioning

confidence: 99%

Effects of Intrathecal Carbenoxolone Treatment on Nociception and Analgesia in Rat

Kamalpour¹,

Fereidoni²,

Moghimi³

2014

Balkan Med J

View full text Add to dashboard Cite

show abstract

“…This topic, which has been reviewed in detail elsewhere, 134,135 is beyond the scope of the present review. It is nonetheless worth pointing out that carbenoxolone, a gap junction inhibitor, reduces neuronal death in focal and global models of ischemia in adult and neonatal rodents.…”

Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 99%

“…It is nonetheless worth pointing out that carbenoxolone, a gap junction inhibitor, reduces neuronal death in focal and global models of ischemia in adult and neonatal rodents. 136 -138 Notably, carbenoxolone was used in the past to treat patients for ulcers 135,139 ; thus, it is tolerated in humans. The actions of carbenoxolone are not specific for gap junctions, however; carbenoxolone also blocks NMDA channels and voltage-sensitive Ca 2ϩ channels, which may influence its effects on ischemic cell death.…”

Section: Astrocytes Cx43 Adenosine and Neuroprotectionmentioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

View full text Add to dashboard Cite

Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

show abstract

“…Indeed, studying Cx36 GJs pharmacologically is complicated by the lack of drugs that act specifically and exclusively on GJs. Mefloquine is the most promising [for review [73]]. Besides being used clinically as an antimalarial drug, MFQ disrupts intracellular calcium [74][75][76], acts as an antagonist at serotonin 5HT3 receptors [77] and also as an acetylcholinesterase inhibitor [78].…”

Section: Discussionmentioning

confidence: 99%

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Shin¹

2013

Biochem & Pharmacol

View full text Add to dashboard Cite

Blockade of gap junctions (GJs) has been shown to reduce seizures in different epilepsy models. Gap junctionmediated, electrically-coupled neuronal networks have been implicated in neuronal synchronization, which is the hallmark of seizure activity. To further understand the role of GJs in seizures, in particular hippocampal seizures, we evaluated electrophysiological responses in the dentate gyrus subfield of the hippocampus, including GABA-mediated recurrent inhibition, seizuregenic stimulation, and seizure activity in response to perforant path kindling in Cx36 knockout (KO) mice compared to wild-type (WT) controls. In anesthetized mice, Cx36 KO mice were characterized by enhanced GABA-mediated recurrent inhibition. Stimulation of the perforant path at 10 Hz for 10 sec (i.e., 100 pulses) markedly enhanced population spike (PS) amplitudes and reduced paired-pulse GABA-mediated inhibition during the stimulation, induced an after discharge for approximately 10 sec at 7-10 sec into the stimulation, and suppressed PS amplitudes postictally for 5-10 min in both KO and WT mice. Repeated epochs of 10 Hz for 10 sec stimulation of the perforant path at 20 min intervals resulted in progressive and persistent disinhibition of paired-pulse responses in WT, but not KO mice. In freely-behaving seizure studies, stimulation of the perforant path (10 Hz for 10 sec) once/day resulted in progressive Stage I-IV seizures in both WT and KO mice. Once Stage IV was achieved, another Stage IV seizure could be elicited each day with the same behavioral response (i.e., Stage V). The threshold for kindled seizures was significantly greater in KO mice compared to WT controls for most stages of seizures. The Cx36 antagonist mefloquine (MFQ) and the typical anticonvulsant pentobarbital reduced Stage IV seizures in both WT and KO mice. Knock-out mice were more sensitive to the anti-epileptic effects of the typical anti-convulsant pentobarbital (20 mg/ kg). Taken together, these findings support the emerging view that reduction in GJ-mediated GABA electrical coupling reduces seizures, perhaps through enhancement of GABAergic feedback inhibition, which results from the uncoupling of the GABA recurrent interneurons from the resistive load that is inherent in their electrical connectivity.

show abstract

Properties of gap junction blockers and their behavioural, cognitive and electrophysiological effects: Animal and human studies

Cited by 191 publications

References 305 publications

Effects of Intrathecal Carbenoxolone Treatment on Nociception and Analgesia in Rat

Effects of Intrathecal Carbenoxolone Treatment on Nociception and Analgesia in Rat

Targeting Astrocytes for Stroke Therapy

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Contact Info

Product

Resources

About