Neuroprotective effects of curcumin via autophagy induction in 6-hydroxydopamine Parkinson's models.

Curcumin, a polyphenolic compound extracted from curcuma longa, acts as a nontoxic matter with anti-oxidant and anti-inflammatory effects as well as antiproliferative activities. Here, our research aimed to explore the neuroprotective effects of curcumin both in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) in vivo and 6-OHDA-lesioned PC12 cells in vitro. In vitro, 6-OHDA caused a distinct decrease in cell viability of PC12 cells (150 µM). With the incubation of curcumin (1 µM), 6-OHDA-induced apoptosis was suppressed, increasing the autophagy markers (LC3-II/LC3-I, Beclin-1) and inhibiting phosphor-AKT/AKT, phosphor-mTOR/mTOR. In vivo, curcumin (50 mg/kg) reduced the accumulation of a-synuclein and led to higher parkinsonian disability scores in 6-OHDA-lesioned PD rats, contributing to induction of autophagy through inhibiting AKT/mTOR signal pathway. Moreover, treatment with autophagy inhibitors, such as 3-MA and chloroquine, abolished the neuroprotective effects of curcumin as evidence by compromised autophagy and declined motor behavior in PD rats. In conclusion, the present study demonstrated that curcumin repressed PC12 cell death in vitro and improved parkinsonian disability scores in vivo by inhibiting AKT/mTOR signaling pathway which mediated by autophagy, indicating a potential value of curcumin in the therapeutic intervention of Parkinson's disease.

Striatal overexpression of ß-arrestin2 counteracts L-dopa-induced dyskinesia in 6-hydroxydopamine lesioned Parkinson's disease rats.

Prolonged administration of Levodopa (L-dopa) therapy can generate L-dopa-induced dyskinesia (LID). Accumulating evidence indicates that hyper-activation of the dopamine D1 receptor (D1R) and the cAMP signaling cascade in the medium spiny neurons (MSNs) of the striatum are involved in LID. Previous studies have shown that striatal ß-arrestin2 overexpression significantly reduces LID severity and have indicated that ß-arrestin2 may play a causal role in the dyskinesia sensitization process. L-dopa-induced changes in the expression of signaling molecules and other proteins in the striatum were examined immunohistochemically and by western blot. A rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablate ß-arrestin2. We found that striatal overexpression of AAV-mediated ß-arrestin2 produced less severe AIMs (abnormal involuntary movements) in response to L-dopa, whereas selective deletion of ß-arrestin2 in the striatal neurons dramatically enhanced the severity of dyskinesia induced by L-dopa. Furthermore, no significant improvements in motor behavior (FFT: forelimb functional test) were seen with the inhibition or overexpression of ß-arrestin2. Finally, overexpression of ß-arrestin2 diminished L-dopa-induced D1R and phosphor-DARPP32/ERK levels. Viral deletion of ß-arrestin2 markedly enhanced the key biochemical markers in the direct pathway. We found that increased availability of ß-arrestin2 ameliorated dyskinesia severity with no influence on the anti-Parkinsonian action of L-dopa, suggesting a promising approach for controlling LID in Parkinson's disease. In addition, overexpression of ß-Arrestin2 prevented the development of LID by inhibiting G protein-dependent D1R and phosphor-DARPP32/ERK signaling in dyskinetic rats.

Levodopa/Benserazide PLGA Microsphere Prevents L-Dopa-Induced Dyskinesia via Lower ß-Arrestin2 in 6-Hydroxydopamine Parkinson's Rats.

Prolonged pulsatile administration of Levodopa (L-dopa) can generate L-dopa-induced dyskinesia (LID). Numerous research has reported that continuous dopamine delivery (CDD) was useful in reducing the severity of LID. 6-OHDA lesioned rats were divided into two groups to receive intermittent L-dopa stimulation (L-dopa/benserazide) or Levodopa/benserazide PLGA microsphere (LBPM) for 3 weeks. rAAV (recombinant adeno-associated virus) vector was used to overexpress and ablation of ß-arrestin2. We found that LBPM developed less AIM severity compared with standard L-dopa administration, whereas selective deletion of ß-arrestin2 in striatum neurons dramatically enhanced the severity of dyskinesia by LBPM. On the contrary, the effects of LBPM in terms of ALO AIM were further relieved by ß-arrestin2 overexpression. Furthermore, no significant change in motor behavior was seen either in inhibition or overexpression of ß-arrestin2. In short, our experiments provided evidence that LBPM's prevention of LID behavior was likely due to ß-arrestin2, suggesting that a therapy modulating ß-arrestin2 may offer a more efficient anti-dyskinetic method with a low risk of untoward effects.

ß-arrestin2 alleviates L-dopa-induced dyskinesia via lower D1R activity in Parkinson's rats.

The cause of the L-dopa-induced dyskinesia (LID) has been ascribed to G-protein coupled receptor (GPCR) supersensitivity and uncontrolled downstream signaling. It is now supposed that ß-arrestin2 affects GPCR signaling through its ability to scaffold various intracellular molecules. We used the rAAV (recombinant adeno-associated virus) vectors to overexpress and ablation of ß-arrestin2. L-dopa-induced changes in expression of signaling molecules and other proteins in the striatum were examined by western blot and immunohistochemically. Our data demonstrated that via AAV-mediated overexpression of ß-arrestin2 attenuated LID performance in 6-OHDA-lesioned rodent models. ß-arrestin2 suppressed LID behavior without compromising the antiparkinsonian effects of L-dopa. Moreover, we also found that the anti-dyskinetic effect of ß-arrestin2 was reversed by SKF38393, a D1R agonist. On the contrary, the rat knockdown study demonstrated that reduced availability of ß-arrestin2 deteriorated LID performance, which was counteracted by SCH23390, a D1R antagonist. These data not only demonstrate a central role for ß-arrestin2/GPCR signaling in LID, but also show the D1R signal pathway changes occurring in response to dopaminergic denervation and pulsatile administration of L-dopa.

A Meta-Analysis of Adenosine A2A Receptor Antagonists on Levodopa-Induced Dyskinesia In Vivo.

BACKGROUND: Long-term use of levodopa (l-dopa) is inevitably complicated with highly disabling fluctuations and drug-induced dyskinesias, which pose major challenges to the existing drug therapy of Parkinson's disease. METHODS: In this study, we conducted a systematic review and meta-analysis to assess the efficacy of A2A receptor antagonists on reducing l-dopa-induced dyskinesias (LID). RESULTS: Nine studies with a total of 152 animals were included in this meta-analysis. Total abnormal involuntary movements (AIM) score, locomotor activity, and motor disability were reported as outcome measures in 5, 5, and 3 studies, respectively. Combined standardized mean difference (SMD) estimates were calculated using a random-effects model. We pooled the whole data and found that, when compared to l-dopa alone, A2A receptor antagonists plus l-dopa treatment showed no effect on locomotor activity (SMD -0.00, 95% confidence interval (CI): -2.52 to 2.52, p = 1.0), superiority in improvement of motor disability (SMD -5.06, 95% CI: -9.25 to -0.87, p = 0.02) and more effective in control of AIM (SMD -1.82, 95% CI: -3.38 to -0.25, p = 0.02). CONCLUSION: To sum up, these results demonstrated that A2A receptor antagonists appear to have efficacy in animal models of LID. However, large randomized clinical trials testing the effects of A2A receptor antagonists in LID patients are always warranted.

Refractive change in the adult rabbit eye after corneal relaxation with the femtosecond laser.

BACKGROUND: A new procedure to correct myopia that does not disturb the cornea in the optical zone and avoids injuring the corneal epithelium could be a key advance in corneal refractive surgery. The aim of this study is to observe the refractive change in the adult rabbits undergoing femtosecond laser-assisted multilayer intrastromal ablation in the mid-periphery of the cornea without injury of epithelium. METHOD: The right eyes of 8 New Zealand White adult rabbits were used for the experiments. A 60-kHz femtosecond laser delivery system was used, and three lamellar layers of laser pulses were focused starting at a corneal depth of 180 µm and ending at 90 µm from the surface, with each successive layer placed 45 µm anterior to the previous layer. In the interface of the applanation contact lens cone, a 6-mm diameter aluminum circle was placed at the center to block the laser, limiting ablation to the mid-periphery of the cornea. The laser settings were as follows: spot/line separation, 10 µm; diameter, 8.0 mm; energy for ablating the stroma, 1.3 µJ. An authorefractor was used to assess the manifest refraction. RESULTS: Mean spherical equivalent (SE) (mean ± SD, SD: standard deviation) was significantly increased at postoperative week 1 (1.67 ± 0.26 D, p < 0.0001), month 1 (1.65 ± 0.23 D, p < 0.0001), and month 3 (1.60 ± 0.22 D, p < 0.0001) compared to baseline (0.68 ± 0.27 D). Mean spherical equivalent showed no significant change between postoperative week 1 and month 3 (p = 0.1168). CONCLUSION: Femtosecond laser-assisted multilayer corneal intrastromal ablation in the mid-periphery may cause a consequent hyperopic shift with no refractive regression.

Comparison study of two diagnostic and grading systems for conjunctivochalasis.

BACKGROUND: Different diagnostic and grading systems of conjunctivochalasis have resulted in apparent disparity between the prevalence rates of recent population-based studies. This study aimed to investigate the disparity between 4-level system cited from Meller and Tseng in 1998 (abbreviated here as Meller's system) and 5-level system modified from Meller's system cited from Zhang and associates (abbreviated here as Zhang's system) regarding the diagnosis and the patients' preferences for the treatment of conjunctivochalasis in the general population. METHODS: A total of 546 senile residents living in the Guiyangyuan community of Shanghai, China, participated in the study. The diagnostic criteria for conjunctivochalasis were based on two diagnostic grading systems: Meller's system and Zhang's system, which was modified from Meller's system. The participants' preference regarding medical treatment for conjunctivochalasis was determined according to the response to a question. One year later, a follow-up interview determines whether the patient had undergone surgery for conjunctivochalasis. RESULTS: With Meller's system, 398 participants were confirmed as having conjunctivochalasis, and the prevalence rate was 72.89%. According to Zhang's system, only 213 participants were diagnosed as having conjunctivochalasis, and the prevalence rate was 39.01%. A total of 109 eyes underwent medical treatment or surgery for conjunctivochalasis in the following year, including eight eyes that were diagnosed as grade II and 101 eyes that were diagnosed as grade III according to Meller's system and five eyes that were diagnosed as grade I, 55 eyes that were diagnosed as grade II, 31 eyes that were diagnosed as grade III, and 18 eyes that were diagnosed as grade IV according to Zhang' system. CONCLUSION: Diagnoses of conjunctivochalasis using Zhang's system are more consistent with patient requests and the medical treatment strategies used than diagnoses made using Meller's system.

Electrocoagulative surgical procedure for treatment of conjunctivochalasis.

The purpose of this study was to present a new procedure to treat symptomatic conjunctivochalasis (CCh) and to evaluate its efficacy. Forty-two patients with symptomatic CCh refractory to medical management were included on this study. Twenty-two patients (n  =  32, eyes; n  =  14 women and n  =  8 men) underwent the new electrocoagulation procedure (group I). Twenty patients (n  =  27 eyes; n  =  11 women and n  =  9 men) underwent crescent-shaped conjunctiva resection (group II). Ocular surface disease index (OSDI) was used to evaluate ocular symptoms. There was a significant difference in mean and SD operation time between group I (8.67 ± 2.07 minutes) and group II (20.45 ± 3.98 minutes; P < 0.0001). OSDI scores (mean ± SD) were significantly lower in group I (28.38 ± 3.14) than group II (31.62 ± 3.17) at postoperative week 2 (P  =  0.0004). No differences in OSDI scores were found between the 2 groups at postoperative week 4 (P  =  0.1749) or 8 (P  =  0.1483). OSDI scores were significantly lower at postoperative week 8 than at baseline in both group I (P  =  0.0002) and group II (P  =  0.0011). Electrocoagulation of the conjunctiva can successfully treat symptomatic CCh with earlier symptomatic attenuation and less operation time than traditional conjunctiva resection.

[The clinical observation of conjunctivochalasis crescent conjunctival resection with bipolar coagulation].

OBJECTIVE: To seek safe, effective, economical, simple treatment conjunctivochalasis surgical methods, optimize treatment, evaluation conjunctivochalasis surgical treatment. METHODS: A prospective randomized control study, 60 patients (60 eyes) conjunctivochalasis surgery patients were randomly divided into two groups, one line of bipolar coagulation therapy, another group of crescent conjunctival resection. After comparing the two surgical methods ocular surface disease index (OSDI) points, the degree of relaxation conjunctiva, tear meniscus height, BUT, surgical complications, the operation time to evaluate the two kinds of surgical methods of clinical efficacy. RESULTS: Bipolar coagulation therapy with crescent conjunctival resection in 8 weeks after the OSDI points, loose conjunctiva residual points, tear meniscus, BUT the difference was not statistically significant. 8 weeks after bipolar coagulation complications points lower than the crescent conjunctival resection is low, the difference was statistically significant (t = 4.67, P = 0.029); bipolar coagulation operating time (9.53 ± 3.15) min crescent than conjunctival resection time (18.59 ± 7.68) min short, the difference was statistically significant (t = 13.26, P > 0.01). CONCLUSIONS: Conjunctivochalasis line bipolar coagulation and removal of loose conjunctiva crescent with considerable effect, bipolar coagulation was significantly shorter operative time, a significant reduction in postoperative complications, surgical procedures easier.

Clinical evaluation of the quantitative locator for conjunctiva resection used as an instrument for the treatment of conjunctivochalasis.

BACKGROUND: The crescent excision of the inferior bulbar conjunctiva has been advised as a surgical procedure in the management of conjunctivochalasis refractory to medical treatments. However, it is difficult for this procedure to design how much conjunctival tissue should be excised. This study aimed to present a quantitative locator for conjunctiva resection and evaluate its effect on the treatment of conjunctivochalasis (CCh). METHODS: Poly ß-hydroxyethyl methacrylate resin/ß-hydroxyethyl methacrylate (HEMA, water gel) was used as the material to make the quantitative locator which was designed to suit the specific patient. Forty-six patients with bilateral symptomatic CCh were included in this prospective study. Of the patients, while the right eye underwent the popularly used crescent-shaped conjunctiva resection (group I), the left eye was treated with conjunctiva resection assisted by the quantitative locator (group II). International Ocular Surface Disease Index (OSDI), scores of remnant conjunctiva fold, complications and conjunctival cut healing, height of tear meniscus, tear break-up time (BUT), and time of surgery were evaluated. Tasting chloromycetin test (TCT) was used to evaluate how the lacrimal duct worked. RESULTS: OSDI in group II (8.82 ± 2.36) was significantly lower than that in group I (14.67 ± 2.21) (t = 12.22, P < 0.01). The amount of conjunctiva fold remaining in group II was less than that in group I. Scores of remnant conjunctiva fold in group I were significantly higher than those in group II (t = 31.85, P < 0.01). While evaluation scores of conjunctival cut healing in group I were lower than those in group II, scores of complication in group I were significantly higher than those in group II at 8 weeks after surgery (t = 89.60, P < 0.01). There was no significant difference in eyes with normal BUT (χ(2) = 0.031, P = 0.985) between the two groups, as the case was in eyes with positive TCT (χ(2) = 0.14, P = 0.930) and in eyes with normal height of tear meniscus (χ(2) = 0.48, P = 0.780). Mean surgery time in group II ((17.11 ± 2.08) minutes) was significantly shorter than that in group I ((25.22 ± 4.78) minutes) (t = 13.84, P < 0.01). CONCLUSION: A quantitative locator can be used as an effective, safe, and less time-consuming instrument to facilitate conjunctival excision for symptomatic CCh treatment.