Yake Zheng

Botulinum toxin type A for the treatment of trigeminal neuralgia: results from a randomized, double-blind, placebo-controlled trial

Aim: To investigate the efficacy, safety and tolerability of intradermal and/or submucosal administration of botulinum toxin type A (BTX-A) for patients with trigeminal neuralgia (TN). Methods: In this randomized, double-blind, placebo-controlled study, 42 TN patients were randomly allocated into two groups, namely, intradermal and/or submucosal injection of BTX-A (75 U/1.5 mL; n = 22) or saline (1.5 mL; n = 20) in the skin and/or mucosa where pain was experienced. The primary endpoints were pain severity (assessed by the visual analogue scale) and pain attack frequency per day. The secondary endpoint was the patient’s overall response to treatment, assessed using the Patient Global Impression of Change scale. Patients with ≥ 50% reduction in mean pain score at week 12 were defined as responders. Results: A total of 40 patients completed the study. BTX-A significantly reduced pain intensity at week 2 and pain attack frequency at week 1. The efficacy was maintained throughout the course of the study. More BTX-A treated patients reported that pain had improved by the end of the study. Significantly more responders were present in the BTX-A group (68.18%) than in the placebo group (15.00%). BTX-A was well tolerated, with few treatment-related adverse events. Conclusions: BTX-A may be an efficient, safe and novel strategy for TN treatment.

Brain-Derived Neurotrophic Factor Ameliorates Learning Deficits in a Rat Model of Alzheimer's Disease Induced by Aβ1-42

An emerging body of data suggests that the early onset of Alzheimer’s disease (AD) is associated with decreased brain-derived neurotrophic factor (BDNF). Because BDNF plays a critical role in the regulation of high-frequency synaptic transmission and long-term potentiation in the hippocampus, the up-regulation of BDNF may rescue cognitive impairments and learning deficits in AD. In the present study, we investigated the effects of hippocampal BDNF in a rat model of AD produced by a ventricle injection of amyloid-β1-42 (Aβ1-42). We found that a ventricle injection of Aβ1-42 caused learning deficits in rats subjected to the Morris water maze and decreased BDNF expression in the hippocampus. Chronic intra-hippocampal BDNF administration rescued learning deficits in the water maze, whereas infusions of NGF and NT-3 did not influence the behavioral performance of rats injected with Aβ1-42. Furthermore, the BDNF-related improvement in learning was ERK-dependent because the inhibition of ERK, but not JNK or p38, blocked the effects of BDNF on cognitive improvement in rats injected with Aβ1-42. Together, our data suggest that the up-regulation of BDNF in the hippocampus via activation of the ERK signaling pathway can ameliorate Aβ1-42-induced learning deficits, thus identifying a novel pathway through which BDNF protects against AD-related cognitive impairments. The results of this research may shed light on a feasible therapeutic approach to control the progression of AD.

Oral administration of grape seed polyphenol extract restores memory deficits in chronic cerebral hypoperfusion rats.

Chronic cerebral hypoperfusion (CCH) has been recognized as an important cause of both vascular dementia and Alzheimer’s disease (AD), the two most prominent neurodegenerative diseases causing memory impairment in the elderly. However, an effective therapy for CCH-induced memory impairment has not yet been established. Grape seed polyphenol extract (GSPE) has powerful antioxidant properties and protects neurons and glia during ischemic injury, but its potential use in the prevention of CCH-induced memory impairment has not yet been investigated. Here, CCH-related memory impairment was modeled in rats using permanent bilateral occlusion of the common carotid artery. A Morris water maze task was used to evaluate memory, the levels of acetylcholinesterase, choline acetyltransferase, acetylcholine were used to evaluate cholinergic function, and oxidative stress was assessed by measuring the enzyme activity of superoxide dismutase, glutathione peroxidase, malonic dialdehyde, and catalase. We found that oral administration of GSPE for 1 month can rescue memory deficits. We also found that GSPE restores cholinergic neuronal function and represses oxidative damage in the hippocampus of CCH rats. We propose that GSPE protects memory in CCH rats by reducing ischemia-induced oxidative stress and cholinergic dysfunction. These findings provide a novel application of GSPE in CCH-related memory impairments.

Ginsenoside Rb1 ameliorates cisplatin-induced learning and memory impairments

Background Ginsenoside Rb1 (Rb1), a dominant component from the extract of Panax ginseng root, exhibits neuroprotective functions in many neurological diseases. This study was intended to investigate whether Rb1 can attenuate cisplatin-induced memory impairments and explore the potential mechanisms. Methods Cisplatin was injected intraperitoneally with a dose of 5 mg/kg/wk, and Rb1 was administered in drinking water at the dose of 2 mg/kg/d to rats for 5 consecutive wk. The novel objects recognition task and Morris water maze were used to detect the memory of rats. Nissl staining was used to examine the neuron numbers in the hippocampus. The activities of superoxide dismutase, glutathione peroxidase, cholineacetyltransferase, acetylcholinesterase, and the levels of malondialdehyde, reactive oxygen species, acetylcholine, tumor necrosis factor-α, interleukin-1β, and interleukin-10 were measured by ELISA to assay the oxidative stress, cholinergic function, and neuroinflammation in the hippocampus. Results Rb1 administration effectively ameliorates the memory impairments caused by cisplatin in both novel objects recognition task and Morris water maze task. Rb1 also attenuates the neuronal loss induced by cisplatin in the different regions (CA1, CA3, and dentate gyrus) of the hippocampus. Meanwhile, Rb1 is able to rescue the cholinergic neuron function, inhibit the oxidative stress and neuroinflammation in cisplatin-induced rat brain. Conclusion Rb1 rescues the cisplatin-induced memory impairment via restoring the neuronal loss by reducing oxidative stress and neuroinflammation and recovering the cholinergic neuron functions.

LncRNA SNHG1 promotes α-synuclein aggregation and toxicity by targeting miR-15b-5p to activate SIAH1 in human neuroblastoma SH-SY5Y cells

HighlightsSNHG1 is upregulated and miR‐15b‐5p is downregulated in PD.SIAH1 promotes &agr;‐synuclein aggregation and toxicity.SIAH1 is a target gene of miR‐15b‐5p.SNHG1 is able to directly bind to miR‐15‐5p and represses miR‐15‐5p expression.SNHG1 promotes &agr;‐synuclein aggregation and toxicity through miR‐15b‐5p/SIAH1 axis. ABSTRACT Numerous long non‐coding RNAs (lncRNAs) have been identified as aberrantly expressed in Parkinsons disease (PD). However, limited knowledge is available concerning the roles of dysregulated lncRNAs and the underlying molecular regulatory mechanism in the pathological process of PD. In this study, we found that lncRNA small nucleolar RNA host gene 1 (SNHG1) and seven in absentia homolog 1 (SIAH1) were upregulated, but microRNA‐15b‐5p (miR‐15b‐5p) was downregulated in SH‐SY5Y cells pretreated with MPP+, as well as in MPTP‐induced mouse model of PD. Overexpression of SIAH1 enhanced cellular toxicity of &agr;‐synuclein in SH‐SY5Y cells, as indicated by the reduction of cell viability and elevation of LDH release. The percentage of &agr;‐synuclein aggregate‐positive cells and the number of &agr;‐synuclein aggregates per cell were increased in SH‐SY5Y cells transfected with pcDNA‐SIAH1, while decreased after transfection with short interfering RNA specific for SIAH1 (si‐SIAH1). Bioinformatics and luciferase reporter assay revealed that SIAH1 was a direct target of miR‐15b‐5p. We also found that SNHG1 could directly bind to miR‐15‐5p and repress miR‐15‐5p expression. Upregulation of miR‐15b‐5p alleviated &agr;‐synuclein aggregation and apoptosis by targeting SIAH1 in SH‐SY5Y cells overexpressing &agr;‐synuclein. Overexpression of SNHG1 enhanced, whereas SNHG1 knockdown inhibited &agr;‐synuclein aggregation and &agr;‐synuclein‐induced apoptosis. Moreover, the neuroprotective effect of si‐SNHG1 was abrogated by downregulation of miR‐15b‐5p. In summary, our data suggest that SNHG1, as a pathogenic factor, promotes &agr;‐synuclein aggregation and toxicity by targeting the miR‐15b‐5p/SIAH1 axis, contributing to a better understanding of the mechanisms of Lewy body formation and loss of dopaminergic neurons in PD.

Treatment of chronic daily headache with comorbid anxiety and depression using botulinum toxin A: a prospective pilot study

Background: Psychiatric comorbidities, including depression and anxiety, are clinical entities associated with chronic daily headache (CDH). Botulinum toxin A (BTA) is a Food and Drug Administration approved drug for the treatment of chronic migraine, a subtype form of CDH. This study aimed to investigate the potential efficacy and safety of BTA for controlling psychiatric symptoms in CDH patients. Methods: A prospective, open-label, pilot study (n = 30; 7 males, 23 females) was performed. A single low-dose of BTA (40–120 U) was injected into the pericranial muscle at multiple sites. Participants were evaluated before and 1, 4, 8, 12, 16, 20 and 24 weeks after BTA treatment. Primary outcomes included: (1) headache severity, determined by a visual analog scale; (2) depression and anxiety severity, assessed via the Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A, respectively); (3) headache frequency per month and (4) single headache episode duration. Results: Headache severity was significantly ameliorated one week after treatment. Depression and anxiety symptoms were significantly reduced one month after treatment. At month four, the headache incidence per month decreased from 28.83 ± 2.95 to 17.57 ± 11.30 d (p < 0.001), and the single headache duration decreased from 12.03 ± 9.47 to 6.63 ± 8.98 h (p < 0.001). Furthermore, the percentage of patients who required analgesics significantly decreased. BTA was well tolerated, and the adverse events were mild and transient. Conclusion: BTA treatment alleviated the severity and frequency of CDH, with improvements in depression and anxiety. These novel findings indicate that BTA may represent an effective and safe intervention to target psychiatric comorbidities in CDH.

Ectopic expression of Miro 1 ameliorates seizure and inhibits hippocampal neurodegeneration in a mouse pilocarpine epilepsy model

Epilepsy is a common disease of the central nervous system. This study aimed to investigate the role of mitochondrial Rho (Miro) 1 in epilepsy, using a mouse model of pilocarpine-induced status epilepticus (SE). Intraperitoneal injection of pilocarpine induced epileptic seizures in mice and significantly decreased Miro 1 expression in the hippocampus. Moreover, pilocarpine treatment increased the serum levels of heat shock protein 70 (HSP70) and S100 calcium binding protein B (S100B) and led to hippocampal neuronal injury and apoptosis. The intrinsic apoptotic pathway was activated in the hippocampal neurons following pilocarpine-induced SE, as evidenced by increased levels of cleaved caspase-3 and Bax, downregulation of Bcl-2, and the release of cytochrome c from mitochondria to cytoplasm. By contrast, forced expression of Miro 1 by lateral ventricular administration of adenovirus mitigated pilocarpine-induced epileptic seizures, reduced the elevation of HSP70 and S100B, and inhibited hippocampal neuronal apoptosis by suppressing the intrinsic apoptotic pathway. In summary, our data demonstrates that ectopic expression of Miro 1 alleviated pilocarpine-induced SE and protected hippocampal neurons by inhibiting the intrinsic apoptotic pathway. These findings provide new insights into epileptic disorders and suggest a potential neuroprotective value of Miro 1 in the treatment of epilepsy.

The expression and significance of tyrosine hydroxylase in the brain tissue of Parkinson's disease rats

The expression and significance of tyrosine hydroxylase (TH) in brain tissue of rats with Parkinsons disease (PD) were explored and analyzed. A total of 120 clean-grade and healthy adult Wistar rats weighing 180–240 g were randomly divided equally into four groups according to the random number table method. Rats were sacrificed before and after the model establishment for 3, 6 or 8 weeks. The number of revolutions in rats was observed and the relative expression of TH mRNA in brain tissue was measured. The relative expression of TH mRNA in left and right brain tissue of normal rats was respectively 1.039±0.112 and 0.956±0.120. There was no significant difference in the expression of TH mRNA in either side of the brain tissue (p>0.05). With the extension of modeling time, the success rate of model establishment was significantly improved (p<0.05). After the model establishment for 6 weeks, the success rate peaked and there was no significant difference with 8 weeks (p>0.05). The relative expression of TH mRNA in the right brain was 0.053±0.082, which was significantly lower than that in the left brain tissue with 1.056±0.094 (p<0.05). After 6 weeks, the relative expression of TH mRNA in the left and right brain of PD rats was respectively 1.004±0.034 and 0.316±0.012, the expression of TH mRNA in right brain tissue was also significantly lower than that in the left (p<0.05). Similarly, after 8 weeks of the model establishment, the relative expression of TH mRNA in the right brain was significantly lower than that in the left brain tissue, with 0.395±0.041 and 1.021±0.057 (p<0.05). Compared with the control group, the expression of TH mRNA in both sides of the brain tissue decreased, and the expression of TH mRNA in the injured brain tissue was significantly lower than that in normal rats (p<0.05). The expression of TH mRNA in brain tissue of PD rats was lower than that in normal brain tissue, which may be related to the occurrence and development of PD.