br GJs in the brain br

GJs in the brain
Alterations of GJs in epilepsy
The role of GJ blockers and openers in epilepsy As previously known, GJ-mediated electrical coupling plays a role in the generation of highly synchronous electrical activity. The hypersynchronous neuronal activity is a significant feature of convulsive events, so it can be speculated that gap junctional communication may be a potential mechanism for epileptogenesis and maintenance. The gap junction blockers and openers can regulate the open or closed state of the GJs, thereby affecting the occurrence of epilepsy. The role of blockade agents such as carbenoxolone, quinine, mefloquine, quinidine, and tonabersat in epilepsy has been reported in epileptic animal models [[134], [135], [136], [137], [138], [139], [140], [141], [142], [143], [144], [145], [146]]. And a lot of reports that studied the relationship between GJ blockers/openers and epileptiform activity were carried out in hippocampal slices or thalamocortical slices. As was reported by scholars in early years, carbenoxolone (a broad-spectrum GJ blocker) and mefloquine decreased the amplitude and duration of seizure-like activity in thalamocortical slices [134,135]. Carbenoxolone could also depress the frequency of spontaneous epileptiform activity in rat hippocampal slices [136]. Interestingly, quinine also observed the similar effects with carbenoxolone in the neocortex in patients with temporal lobe epilepsy [137,138]. Besides, spontaneous synchronous events generated by application of 4-aminopyridine in neocortical slices from temporal lobe epileptic patients was also decreased by carbenoxolone [137]. Also, antiepileptic effects of other GJ blockers have been reported. Quinine, as a potent gap junction blocker, depressed GABAergic ictal-like events in rat hippocampal slices exposed to GABA(B) jasplakinolide antagonists [139]. And quinidine abolished the ictal-like activities in rat thalamocortical slices induced by 4-aminopyridine [140]. 1-heptanol and 1-octanol had been reported to significantly depress all the epileptiform markers of the evoked responses induced in CA3 area of rat hippocampal slices by a high K+-low Ca2+ perfusion fluid [141]. Tonabersat, a novel cis benzopyran derivative, is used for the treatment of migraine and epilepsy [[142], [143], [144]]. A previous study reported that tonabersat could elevate the threshold for PTZ-induced tonic forelimb extension seizures [145]. Meanwhile, tonabersat was observed to prevent inflammatory damage via blocking Cx43 hemichannels in vitro ischemia-reperfusion model [146]. Therefore, skin is possible that tonabersat may exert anti-epileptic effect by suppressing Cx43 hemichannels. On the contrary, trimethylamine, a GJ opener, increased secondary and tertiary discharges induced by Mg2+-free solution [147]. As well as, trimethylamine significantly enhanced seizure-like activity induced by 4-AP and bicuculline [135]. Similarly, ammonium chloride increases the frequency and duration of spontaneous field activity in the Ca2+-free model of epilepsy [148]. In addition to the studies in the in vitro model, increasing evidence from in vivo experimental studies also indicates that GJs are involved in the epileptiform activity. In the kainic acid-kindled rats, carbenoxolone, quinine, and quinidine reversed the overexpression of MAP-2 and SYP and led to the inhibition of propagation of seizure activity [149]. According to the report, fast ripples are considered to be potential biomarkers for epilepsy [150,151]. Carbenoxolone reduced the average number of oscillation cycles per fast ripples event in the hippocampus of rats with spontaneous seizures induced by pilocarpine [151]. Carbenoxolone could significantly decrease the spectral power and the amplitude of the epileptiform activity induced by PTZ [152]. Similarly, in the PTZ-induced epilepsy model, quinine could attenuate seizure severity and the mean seizure stages at different doses compared with the control [151]. In addition, quinine could inhibit epileptiform activity by decreasing the amplitude and frequency of epileptiform spikes [153] (Table 2).