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Vincamine exerts protective effect on spiral ganglion neurons in endolymphatic hydrops guinea pig models.

ABSTRACT: The aim of this study was to investigate the protective effects of vincamine in endolymphatic hydrops (ELH). After ELH guinea pigs treated by vincamine, the concentration of VAP in plasma, and the levels of cAMP, MDA, SOD, GSH-Px in right cochlea were measured using spectrophotometric method. The V2R, NMDAR1, p-NMDAR1, AQP2, p-AQP2, caspase3/9 and c-caspase3/9 expressions in right cochlea were detected using western blot analysis. The cochlear hydrops degree and SGNs density were evaluated by hemotoxylin and eosin staining (HE) test. Normal hearing and vestibular function were warranted by the tests of auditory brainstem response (ABR) and electronystagmography (ENG). After glutamate-injured SGNs treated with vincamine, the MDA, SOD GSH-Px, NGF, BDNF, NT3, NT4 and Trks levels were measured. Meanwhile, the Bcl2, Bax, NMDAR1, p-NMDAR1, PI3K, p-PI3K, Akt, p-Akt, caspase3/9 and cleaved-caspase3/9 expression levels were detected. Furthermore, the viability, apoptosis and necrosis of SGNs were tested by MTT and Hoechst/PI staining methods. The results indicated that vincamine could significantly inhibit the expression levels of cAMP, MDA, V2R, p-NMDAR1, p-AQP2 and c-caspase-3/-9 in cochlea, alleviate the cochlear hydrops degree, regulate the audiological and vestibular dysfunctions. The SGNs density, SOD and GSH-Px levels were also increased by vincamine. In vincamine-treating groups, the MDA, Bax, p-NMDAR1, and c-caspase3/9 levels were observably decreased, while SGNs survival, SOD, GSH, NGF, BDNF, NT3, NT4, Trks, Bcl2, p-PI3K, p-Akt expressions were improved. The present study indicated a novel use of vincamine in suppressing ELH formation by down-regulating the VAP/AQP2 signaling pathway. It also manifested that vincamine exerted protective effects on hearing via improving neurotrophin-dependent PI3K/Akt signaling pathway in SGNs.

SUBMITTER: Li Y

PROVIDER: S-EPMC6291722 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:For long it was believed that a particular population of enteric neurons, referred to as intrinsic primary afferent neuron (IPAN)s, encodes mechanical stimulation. We recently proposed a new concept suggesting that there are in addition mechanosensitive enteric neurons (MEN) that are multifunctional. Based on firing pattern MEN behaved as rapidly, slowly, or ultra-slowly adapting RAMEN, SAMEN, or USAMEN, respectively. We aimed to validate this concept in the myenteric plexus of the gastric corpus, a region where IPANs were not identified and existence of enteric sensory neurons was even questioned. The gastric corpus is characterized by a particularly dense extrinsic sensory innervation. Neuronal activity was recorded with voltage sensitive dye imaging after deformation of ganglia by compression (intraganglionic volume injection or von Fry hair) or tension (ganglionic stretch). We demonstrated that 27% of the gastric neurons were MEN and responded to intraganglionic volume injection. Of these 73% were RAMEN, 25% SAMEN, and 2% USAMEN with a firing frequency of 1.7 (1.1/2.2), 5.1 (2.2/7.7), and of 5.4 (5.0/15.5) Hz, respectively. The responses were reproducible and stronger with increased stimulus strength. Even after adaptation another deformation evoked spike discharge again suggesting a resetting mode of the mechanoreceptors. All MEN received fast synaptic input. Fifty five percent of all MEN were cholinergic and 45% nitrergic. Responses in some MEN significantly decreased after perfusion of TTX, low Ca(++)/high Mg(++) Krebs solution, capsaicin induced nerve defunctionalization and capsazepine indicating the involvement of TRPV1 expressing extrinsic mechanosensitive nerves. Half of gastric MEN responded to intraganglionic volume injection as well as to ganglionic stretch and 23% responded to stretch only. Tension-sensitive MEN were to a large proportion USAMEN (44%). In summary, we demonstrated for the first time compression and tension-sensitive MEN in the stomach; many of them responded to one stimulus modality only. Their proportions and the basic properties were similar to MEN previously identified by us in other intestinal region and species. Unlike in the intestine, the responsiveness of some gastric MEN is enhanced by extrinsic TRPV1 expressing visceral afferents.

Project description:Objective: Intravenous contrast agent enhanced, high-resolution magnetic resonance imaging of the inner ear (iMRI) confirmed that patients with Menière's disease (MD) and vestibular migraine (VM) could present with endolymphatic hydrops (EH). The present study aimed to investigate EH characteristics and their interrelation to neurotologic testing in patients with VM, MD, or VM with concurrent MD (VM-MD). Methods: Sixty-two patients (45 females, aged 23-81 years) with definite or probable VM (n = 25, 19 definite), MD (n = 29, 17 definite), or showing characteristics of both diseases (n = 8) were included in this study. Diagnostic workup included neurotologic assessments including video-oculography (VOG) during caloric stimulation and head-impulse test (HIT), ocular and cervical vestibular evoked myogenic potentials (o/cVEMP), pure tone audiometry (PTA), as well as iMRI. EH's degree was assessed visually and via volumetric quantification using a probabilistic atlas-based segmentation of the bony labyrinth and volumetric local thresholding (VOLT). Results: Although a relevant number of VM patients reported varying auditory symptoms (13 of 25, 52.0%), EH in VM was only observed twice. In contrast, EH in VM-MD was prevalent (2/8, 25%) and in MD frequent [23/29, 79.3%; χ2(2) = 29.1, p < 0.001, φ = 0.7]. Location and laterality of EH and neurophysiological testing classifications were highly associated (Fisher exact test, p < 0.005). In MD, visual semi-quantitative grading and volumetric quantification correlated highly to each other (r S = 0.8, p < 0.005, two-sided) and to side differences in VOG during caloric irrigation (vestibular EH ipsilateral: r S = 0.6, p < 0.05, two-sided). In VM, correlations were less pronounced. VM-MD assumed an intermediate position between VM and MD. Conclusion: Cochlear and vestibular hydrops can occur in MD and VM patients with auditory symptoms; this suggests inner ear damage irrespective of the diagnosis of MD or VM. The EH grades often correlated with auditory symptoms such as hearing impairment and tinnitus. Further research is required to uncover whether migraine is one causative factor of EH or whether EH in VM patients with auditory symptoms suggests an additional pathology due to MD.

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Vincamine exerts protective effect on spiral ganglion neurons in endolymphatic hydrops guinea pig models.

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