Network pharmacology analysis and animal experiment validation of neuroinflammation inhibition by total ginsenoside in treating CSM.

BACKGROUND: Cervical spondylotic myelopathy (CSM) is a degenerative pathology that affects both upper and lower extremity mobility and sensory function, causing significant pressure on patients and society. Prior research has suggested that ginsenosides may have neuroprotective properties in central nervous system diseases. However, the efficacy and mechanism of ginsenosides for CSM have yet to be investigated. PURPOSE: This study aims to analyze the composition of ginsenosides using UPLC-MS, identify the underlying mechanism of ginsenosides in treating CSM using network pharmacology, and subsequently confirm the efficacy and mechanism of ginsenosides in rats with chronic spinal cord compression. METHODS: UPLC-Q-TOF-MS was utilized to obtain mass spectrum data of ginsenoside samples. The chemical constituents of the samples were analyzed by consulting literature reports and relevant databases. Ginsenoside and CSM targets were obtained from the TCMSP, OMIM, and GeneCards databases. GO and KEGG analyses were conducted, and a visualization network of ginsenosides-compounds-key targets-pathways-CSM was constructed, along with molecular docking of key bioactive compounds and targets, to identify the signaling pathways and proteins associated with the therapeutic effects of ginsenosides on CSM. Chronic spinal cord compression rats were intraperitoneally injected with ginsenosides (50 mg/kg and 150 mg/kg) and methylprednisolone for 28 days, and motor function was assessed to investigate the therapeutic efficacy of ginsenosides for CSM. The expression of proteins associated with TNF, IL-17, TLR4/MyD88/NF-κB, and NLRP3 signaling pathways was assessed by immunofluorescence staining and western blotting. RESULTS: Using UPLC-Q-TOF-MS, 37 compounds were identified from ginsenoside samples. Furthermore, ginsenosides-compounds-key targets-pathways-CSM visualization network indicated that ginsenosides may modulate the PI3K-Akt signaling pathway, TNF signaling pathway, MAPK signaling pathway, IL-17 signaling pathway, Toll-like receptor signaling pathway and Apoptosis by targeting AKT1, TNF, MAPK1, CASP3, IL6, and IL1B, exerting a therapeutic effect on CSM. By attenuating neuroinflammation through the TNF, IL-17, TLR4/MyD88/NF-κB, and MAPK signaling pathways, ginsenosides restored the motor function of rats with CSM, and ginsenosides 150 mg/kg showed better effect. This was achieved by reducing the phosphorylation of NF-κB and the activation of the NLRP3 inflammasome. CONCLUSIONS: The results of network pharmacology indicate that ginsenosides can inhibit neuroinflammation resulting from spinal cord compression through multiple pathways and targets. This finding was validated through in vivo tests, which demonstrated that ginsenosides can reduce neuroinflammation by inhibiting NLRP3 inflammasomes via multiple signaling pathways, additionally, it should be noted that 150 mg/kg was a relatively superior dose. This study is the first to verify the intrinsic molecular mechanism of ginsenosides in treating CSM by combining pharmacokinetics, network pharmacology, and animal experiments. The findings can provide evidence for subsequent clinical research and drug development.

Astaxanthin promotes locomotor function recovery and attenuates tissue damage in rats following spinal cord injury: a systematic review and trial sequential analysis.

Spinal cord injury (SCI) is a catastrophic condition with few therapeutic options. Astaxanthin (AST), a natural nutritional supplement with powerful antioxidant activities, is finding its new application in the field of SCI. Here, we performed a systematic review to assess the neurological roles of AST in rats following SCI, and assessed the potential for clinical translation. Searches were conducted on PubMed, Embase, Cochrane Library, the Web of Science, China National Knowledge Infrastructure, WanFang data, Vip Journal Integration Platform, and SinoMed databases. Animal studies that evaluated the neurobiological roles of AST in a rat model of SCI were included. A total of 10 articles were included; most of them had moderate-to-high methodological quality, while the overall quality of evidence was not high. Generally, the meta-analyses revealed that rats treated with AST exhibited an increased Basso, Beattie, and Bresnahan (BBB) score compared with the controls, and the weighted mean differences (WMDs) between those two groups showed a gradual upward trend from days 7 (six studies, n = 88, WMD = 2.85, 95% CI = 1.83 to 3.87, p < 0.00001) to days 28 (five studies, n = 76, WMD = 6.42, 95% CI = 4.29 to 8.55, p < 0.00001) after treatment. AST treatment was associated with improved outcomes in spared white matter area, motor neuron survival, and SOD and MDA levels. Subgroup analyses indicated there were differences in the improvement of BBB scores between distinct injury types. The trial sequential analysis then firmly proved that AST could facilitate the locomotor recovery of rats following SCI. In addition, this review suggested that AST could modulate oxidative stress, neuroinflammation, neuron loss, and autophagy via multiple signaling pathways for treating SCI. Collectively, with a protective effect, good safety, and a systematic action mechanism, AST is a promising candidate for future clinical trials of SCI. Nonetheless, in light of the limitations of the included studies, larger and high-quality studies are needed for verification.

Degeneration of saccular hair cells caused by MITF gene mutation.

BACKGROUND: Waardenburg syndrome (WS) is the consequence of an inherited autosomal dominant mutation which causes the early degeneration of intermediate cells of cochlear stria vascularis (SV) and profound hearing loss. Patients with WS may also experience primary vestibular symptoms. Most of the current WS studies did not discuss the relationship between WS and abnormal vestibular function. Our study found that a spontaneous mutant pig showed profound hearing loss and depigmentation. MITF-M, a common gene mutation causes type WS which affect the development of the intermediate cell of SV, was then identified for animal modeling. RESULTS: In this study, the degeneration of vestibular hair cells was found in pigs with MITF-M. The morphology of hair cells in vestibular organs of pigs was examined using electron microscopy from embryonic day E70 to postnatal two weeks. Significant hair cell loss in the mutant saccule was found in this study through E95 to P14. Conversely, there was no hair cell loss in either utricle or semi-circular canals. CONCLUSIONS: Our study suggested that MITF-M gene mutation only affects hair cells of the saccule, but has no effect on other vestibular organs. The study also indicated that the survival of cochlear and saccular hair cells was dependent on the potassium release from the cochlear SV, but hair cells of the utricle and semi-circular canals were independent on SV.

[Analysis of clinical features of concomitant vertigo in idiopathic sudden deafness].

OBJECTIVE: To analyze the clinical characteristics of concomitant vertigo in patients with sudden deafness (SD). METHODS: Ninety-six cases of SD were reviewed retrospectively from January 2005 to July 2009. SD and benign paroxysmal positional vertigo (BPPV) were diagnosed according to the guides of China Medical Association. The characteristics of vestibular function and the order of the onset of cochlear and vestibular symptoms were analyzed. RESULTS: Of all 96 cases, 23 (24.0%) cases presented with BPPV; 58 (60.4%) cases took the form of unilateral vestibular hypofunction and 15 (15.6%) cases had normal vestibular function. Time interval between cochlear and vestibular symptoms was as follows: 46 patients could tell the exact time of onset of cochlear and vestibular symptoms, of which 6 (13.0%) cases occurred simultaneously; 4 (8.7%) cases presented vertigo within 1 hour after onset of cochlear symptom hypofunction; 21 (45.7%) cases showed time interval between 1 hour and 24 hours; and 13 (28.3%) cases presented vertigo at several days (less than 10 days) after cochlear symptoms. And only in 2 (4.3%) cases did vertigo occur before cochlear symptoms. CONCLUSIONS: Concomitant vertigo in idiopathic SD took the forms of normal or abnormal vestibular function, some of which were BPPV. Occurrence of vertigo was after cochlear symptoms.

[Complications of canalith repositioning procedure for benign paroxysmal positional vertigo].

OBJECTIVE: To investigate the incidence of complications of canalith repositioning procedure (CRP) for benign paroxysmal positional vertigo (BPPV) in order to recognize and intervene the complication. METHODS: Totally 430 cases of BPPV were treated by CRP between Jan., 2005 and Nov., 2007. The patients with complication were retreated with CRP according to the new canals otolith falling into. RESULTS: There were 313 patients with posterior canal BPPV, among which 5 had complications during CRP for posterior canal BPPV and 3 for horizontal canal BPPV. And 1 patient transformed from cupulolithiasis to canalithiasis during Semont CRP, which made CRP possible. Three patients had horizontal BPPV during CRP for posterior canal BPPV. Horizontal BPPV emerged during CRP for anterior canal BPPV in 1 patient. CRP for the posterior BPPV had more patients with complication than that of CRP for the anterior BPPV, but the percentage was on the contrary, and they were 1.9% (8/313) and 28.6% (2/7) respectively. The rate of complication during CRP was 3.3% (14/430) and all of them recovered well with CRP. CONCLUSIONS: There are possibility for canal otolith transferred from one canal to another. Careful observation of nystagmus and reevaluation of the patients with BPPV in case of unsuccessful treatments are crucial to determine the complications.

[Visual evoked potentials in adults with migrainous vertigo].

OBJECTIVE: To investigate the visual evoked potentials in adults with migrainous vertigo (MV). METHODS: Totally 113 patients with MV were enrolled from vertigo clinic. Patients received necessary laboratory examinations as well as pattern visual evoked potential (PVEP) testing. RESULTS: Definite MV accounted for 46.9% (53/113) and probable MV accounted for 53.1% (60/113). Among 74 patients who received PVEP, the results were normal in 35 patients (47.3%) and abnormal in 39 patients (52.7%). The abnormal manifestations included lowered N75-P100 amplitude, elongated latency of P100, and lowered N75-P100 amplitude combined with delayed latency of P100. Seven patients with MV had unilateral lowered N75-P100 amplitude and 4 had bilateral abnormal amplitude. Nine patients had unilateral delayed latency of P100 and 11 had bilateral abnormal latency. Four patients had unilateral and 4 had bilateral abnormal N75-P100 amplitude and latency of P100. CONCLUSIONS: MV patients usually have abnormal PVEP. PVEP may become a useful electrophysiological test in the diagnosis of MV.

[Pathogenesis of benign paroxysmal positional vertigo].

OBJECTIVE: To explore the etiological factors of benign paroxysmal positional vertigo (BP-PV). METHODS: The clinical data of 145 patients with BPPV were retrospectively reviewed. The impacts of gender and age on BPPV were analyzed. The relationship between the onset of BPPV and the internal ear ischemia was also explored. RESULTS: The abnormality rate of auditory brainstem response (ABR) under high stimulus rate was 59.3% (86/145) in all the patients with, including 22.1% (32/145) in male and 37.2% (54/ 145) in female (P > 0.05). The abnormality rate of ABR under high stimulus rate were 37.9% (55/145) and 21.4% (31/145) in middle-aged (30-55 years) and old ( > 55 years) patients, respectively (P > 0.05). CONCLUSION: The onset of BPPV may relate to ischemic internal ear but is not relevant with gender and age.

[Benign paroxysmal positioning vertigo related to inner ear disorders].

OBJECTIVE: To investigate the incidence of benign paroxysmal positional vertigo(BPPV) and to further understand the possible mechanism of BPPV. METHODS: To observe the incidence of BPPV among vestibular neuritis, sudden deafness, Meniere's disease and Bell's palsy at vertigo clinic from January at 2004 to November at 2006 and to compare the therapeutic results with that of the primary BPPV. RESULTS: There are 4 types of inner ear disorders involved in the concomitant BPPV, ie, vestibular neuritis, sudden deafness, Meniere's disease and Bell's palsy and the incidence are 9.5% (5/53), 38.9% (35/90) and 0.3% (1/381) respectively; and there was 1 case of BPPV concomitant to Bell's palsy. Among the 42 concomitant BPPV, 5 cases were horizontal canal BPPV, 37 cases were posterior canal BPPV, and 1 cases had complicated anterior BPPV during repositioning maneuver. 39 cases of concomitant BPPV were canalithiasis and 3 cases were cupuliothiathitis, of which 75% (27/36) of concomitant BPPV emerged within 1/2 years after the onset of primary inner ear disorders. The therapeutic efficacy of the concomitant BPPV with canalith repositioning was similar to that of the primary type of BPPV. CONCLUSIONS: Following some inner ear disorder, BPPV could emerge, such as sudden deafness, vestibular neuritis and Meniere's disease. The most common type of BPPV was canalithiasis of posterior canal, and the cupulolithiasis of horizontal canal was uncommon. The anterior canal therapeutic efficacy of the concomitant BPPV with canalith repositioning was similar to that of the primary type of BPPV. The therapeutic efficacy of the concomitant BPPV with canalith repositioning was similar to that of the primary type of BPPV.

[Neurootological manifestation of migrainous vertigo].

OBJECTIVE: To analyzed the characteristics of migrainous vertigo (MV), a kind of paroxysmal vertigo, in order to demonstrate the extent of damage and dysfunction in MV and to judge whether MV is peripheral or central vertigo. METHODS: Twenty-two cases of acute (5 cases) or subacute (17 cases) MV were examined with oto-neurological tests, spontaneous nystagmus, positional nystagmus and auditory tests. RESULTS: There were 6 males and 16 females. Among those patients, 15 had migraine, 17 motion sickness, 15 family history of migraine or motion sickness, 1 visual aura, 7 motion intolerance (vertigo from head movement and body movement), 4 photophobia, 6 phonophobia and 5 vertigo from insomnia and emotion. There were likely to have vertigo in menstrual period in 2 cases. The duration of vertigo lasted from minutes to days. For pure-tone audiometric, 9 were normal which from mild to moderate hearing loss. Three cases had abnormal high frequency ABR bilaterally and 10 abnormal unilaterally. Subjective visual vertical were normal in all of the cases. Vestibular evoked myogenic potentials were abnormal in 14 cases (13 had low amplitude and 1 had longer latency of P13 wave). Bithermal caloric test was abnormal in 3 cases and 11 had abnormal ocular movement (9 with low gain of optokinetic nystagmus, 1 with overshoot in saccade and 1 with vertical nystagmus after head shaking), in which 10 had abnormal high frequency ABR and 1 was normal. CONCLUSIONS: MV could be peripheral or central vertigo and MV should be included in the differentiation of peripheral and central vertigo.

[Clinical significance of vibration-induced nystagmus in patients with unilateral peripheral vestibular disorders].

OBJECTIVE: To clarify the clinical significance of vibration-induced nystagmus (VIN) and to calculate the sensitivity and the specificity of the vibration test. METHODS: One hundred and twelve patients with unilateral peripheral vestibular disorders and 30 normal subjects were enrolled into this study. However, patients with spontaneous nystagmus were excluded. Vibratory stimuli (approximately 92Hz) were presented to the mastoids and the forehead. Patients and normal subjects also underwent head shaking testing and caloric testing. RESULTS: Of the 112 patients, 91 (81%) showed VIN which were mainly horizontal. VIN was more frequently evoked on the mastoids than on the forehead. In the majority of patients (76 cases), the direction of VIN was toward the healthy side, whereas patients with Meniere's disease (15 cases), showed nystagmus toward the affected side. None of 30 normal subjects showed VIN. Whereas, HSN was found in 70 (63%) patients and 9 (30%) in normal subjects. Of 112 patients, 10 showed a canal paresis (CP) value of caloric test less than 25% ,while 32 with a CP value between 25% and 40%, 48 with a CP value between 40% and 70%, and 22 with a CP value more than 70%. It is notable that with increasing canal paresis value on caloric testing, VIN was more likely to be evoked. CONCLUSIONS: VIN testing is a simple, non-invasive and well-tolerated clinical test that indicates unilateral peripheral vestibular dysfunction. VIN testing had greater sensitivity and the specificity than HSN testing in the diagnosis of unilateral peripheral vestibular disorders.

[Audio-vestibular function in patients with benign paroxysmal positional vertigo].

OBJECTIVE: To investigate the audio-vestibular function and the possible mechanism of benign paroxysmal positional vertigo (BPPV) and to raise the therapeutic strategy. METHODS: Patients with BPPV were tested with pure tone audiometry, high frequency ABR audiometry, bithermal caloric test and vestibular evoked myogenic potential test (VEMP). The positive rate of these otologic function test were analyzed. RESULTS: Primary BPPV comprised 82 percent (70/86) of patients with BPPV. Among all of the patients, the results of pure tone audiometry were abnormal in 52 percent (45/86) of the cases. High frequency auditory brainstem response (ABR) was abnormal in 60 percent (30/50) of cases. Vestibular evoked myogenic potential (VEMP) was abnormal in 34 percent (11/32) of cases who had this examination. And bithermal caloric test were abnormal in 28 percent (20/72) of cases. In the abnormal cases, 67 percent (12/18) of cases were ipsilateral with BPPV. The majority of the BPPV with abnormal results of bithermal caloric test (89%, 16/18) belong to posterior semicircular canal BPPV. CONCLUSIONS: The incidence of primary BPPV was higher than that of secondary BPPV. The abnormality in superior labyrinth was much more correlated with the occurrence of BPPV. The inner ear ischemia might be a factor in the morbidity of BPPV, especially for the primary BPPV.

Relationship between the external aperture and hearing loss in large vestibular aqueduct syndrome.

BACKGROUND: Large vestibular aqueduct syndrome (LVAS) is a major cause of hearing loss in childhood. This study aimed at measuring external aperture of enlargement of the vestibular aqueduct (EVA) and analyzing relationship between the size of external aperture and hearing loss. METHODS: Diagnostic criteria of LVAS were based on hearing loss and CT images. CT images of temporal bone of 100 LVAS patients were collected and 60 control subjects were reviewed retrospectively in the past 10 years. A battery of audiometric and vestibular function tests were performed. The width of the vestibular aqueduct (VA) was measured on axial CT images of the temporal bone. RESULTS: One hundred patients (65 men, 35 women) were diagnosed as having the isolated EVA. Hearing loss mostly occurred in early childhood. The diagnosis age of LVAS was 7.7 years on average. The causes of hearing loss could not be confirmed by initial consult. Typically, audiometric curve is the high-frequency down-sloping configuration. 92% of the cases had severe or profound sonsorineural hearing loss (SNHL). The mean size of the external aperture was (7.5 +/- 1.2) mm in present LVAS. Statistical analysis showed that the degree of hearing loss is unrelated to the width of VA. CONCLUSIONS: LVAS is a distinct clinical entity characterized by fluctuating, progressive SNHL. The degree of hearing loss is unrelated to the size of external aperture of VA. The protective management and hearing aid have become the main therapies. The cochlear implantation might be performed if the hearing loss affected learning at school.

[Cross-check of caloric test and head shaking nystagmus].

OBJECTIVE: To investigate the manifestation of head shaking nystagmus (HSN) and the relationship between HSN and vestibular bithermal test while cross-checking the HSN and vestibular bithermal test. METHODS: One hundred and twenty-four patients were examined by HSN and vestibular bithermal test. The latency and duration of HSN were observed and the dynamic changes of HSN were also investigated. The results of bithermal test were clarified by the values of canal paresis (CP). RESULTS: There were 3 types of HSN, including 41 monophasic HSN, 11 biphasic HSN and 7 perverted HSN. The latency of monophasic HSN was (2.75 +/- 1.41) ms and the duration of it was (32.16 +/- 20.30) ms; as for the biphasic HSN, the first phase had no latency and the duration was (12.33 +/- 4.42) ms which was shorter than that of the second phase (57.00 +/- 17.19) ms (P < 0.01) and the latency of second phase was (57.00 +/- 17.19) ms. The value of canal paresis in the patients without HSN was lower than that in the patients with HSN. CONCLUSIONS: The existence of HSN was dependent on the loss of the function horizontal canal and also on the stage of vestibular compensation. The variation of duration of HSN among individuals was great. In the acute stage of unilateral vestibular function loss, there appeared to be prominent HSN, and the direction of HSN is the same as that of spontaneous nystagmus. With the development of vestibular compensation, biphasic nystagmus would appear instead of monophasic HSN and the direction of first phase represent the direction of un-lesioned side. After compensation, HSN would not be elicited. However,when HSN existed, it suggested that the value of CP should exceed 25%. Perverted nystagmus pointed to central abnormality.

[Design and preliminary use of the device of subjective visual vertical].

OBJECTIVE: The device of subjective visual vertical (SVV) was made to test the gravity orientation of subjects visual. METHODS: The normative value was established firstly in the right, left and both eyes respectively. Then the test was applied to evaluate the function of otolith function (utricular function) in normal adult subjects and examined the SVV in some patients suffered from acute unilateral vestibulopathy. RESULTS: The difference of the SVV among right, left and both eyes was not significant and the normative value was lower than +/- 2 degrees. No matter one eye or both eyes, SVV had the tendency to lateraliseze to the right. CONCLUSIONS: The SVV is a reliable choice to test the otolith vestibulopathy, which is at least suitable for acute phase. The bilateral eyes open mode is recommended to test the subjects suspected of utricuar dysfunction.

[Characteristics of the response of vestibular evoked myogenic potentials to different stimulus modes].

OBJECTIVE: Vestibular evoked myogenic potential (VEMP) has been utilized in clinic to test the function of saccule. In the present study, 3 stimulus modes were applied to 21 normal adults and intended to draw in a clinical test protocol. METHODS: The normal latency and amplitude of VEMPs of 21 normal subjects were recorded and the ratio of bilateral amplitudes and asymmetry were calculated. RESULTS: The response to binaural clicks were similar to the response of the monaural clicks. The interindividual variation in amplitude were large, but the latency varied little. CONCLUSIONS: VEMPs is a stable myogenic potentials. Monaural and binaural clicks stimulus can be used in clinical practice. The latter is appropriate for normal hearing subjects. Amplitude measurement is probable to evaluate the asymmetry of bilateral saccular function and may reveal saccule lesion.

[Inferior vestibular nerve impairment in auditory neuropathy].

OBJECTIVE: To investigate if auditory neuropathy have inferior vestibular nerve (IVN) lesion and to explore the relation between AN and the IVN lesion by vestibular evoked myogenic potentials (VEMPs). METHODS: VEMPs were observed in 13 patients with auditory neuropathy. And the relation among the duration, hearing threshold of lower frequency and speech discrimination score with VEMPs were observed. RESULTS: Fifty-four percent patients in auditory neuropathy had abnormal VEMPs. They took the form of lower amplitude and no response. The statistical analysis showed that the abnormality of VEMPs had no correlation with lower frequency hearing loss, the duration and speech discrimination score. CONCLUSIONS: The IVN dysfunction may coexist with auditory neuropathy, having lesion in the IVN. However, there was no significant relation between the severity of AN and VEMPs, which meant that AN and inferior vestibular neuropathy had their independence to some extent.