Safety and effectiveness of lurasidone in the treatment of Chinese schizophrenia patients: An interim analysis of post-marketing surveillance.

BACKGROUND: Schizophrenia is a psychiatric disorder characterized by chronic or recurrent symptoms. Lurasidone was licensed in China in 2019 for the treatment of adult schizophrenia in adults with a maximum dose of 80 mg/d. However, post-market surveillance (PMS) with an adequate sample size is required for further validation of the drug's safety profile and effectiveness. AIM: To conduct PMS in real-world clinical settings and evaluate the safety and effectiveness of lurasidone in the Chinese population. METHODS: A prospective, multicenter, open-label, 12-wk surveillance was conducted in mainland China. All patients with schizophrenia from 10 sites who had begun medication with lurasidone between September 2019 and August 2022 were eligible for enrollment. Safety assessments included adverse events (AEs), adverse drug reactions (ADRs), extrapyramidal symptoms (EPS), akathisia, use of EPS drugs, weight gain, and laboratory values as metabolic parameters and the QTc interval. The effectiveness was assessed using the brief psychiatric rating scale (BPRS) from baseline to the end of treatment. RESULTS: A total of 965 patients were enrolled in the full analysis set and 894 in the safety set in this interim analysis. The average daily dose was 61.7 ± 19.08 mg (mean ± SD) during the treatment. AEs and ADRs were experienced by 101 patients (11.3%) and 78 patients (8.7%), respectively, which were mostly mild. EPS occurred in 25 individuals with a 2.8% incidence, including akathisia in 20 individuals (2.2%). Moreover, 59 patients received drugs for treating EPS during the treatment, with an incidence of 6.6% which dropped to 5.4% at the end of the treatment. The average weight change was 0.20 ± 2.36 kg (P = 0.01687) with 0.8% of patients showing a weight gain of ≥ 7% at week 12 compared with that at the baseline. The mean values of metabolic parameters and the QTc interval at baseline and week 12 were within normal ranges. The mean changes in total BPRS scores were -8.9 ± 9.76 (n = 959), -13.5 ± 12.29 (n = 959), and -16.8 ± 13.97 (n = 959) after 2/4, 6/8, and 12 wk, respectively (P < 0.001 for each visit compared with the baseline) using the last-observation-carried-forward method. CONCLUSION: The interim analysis of the PMS of adult patients with schizophrenia demonstrate the safety and effectiveness of lurasidone in the Chinese population. No new safety or efficacy concerns were identified.

Mutually exclusive substrate selection strategy by human m3C RNA transferases METTL2A and METTL6.

tRNAs harbor the most diverse posttranscriptional modifications. The 3-methylcytidine (m3C) is widely distributed at position C32 (m3C32) of eukaryotic tRNAThr and tRNASer species. m3C32 is decorated by the single methyltransferase Trm140 in budding yeasts; however, two (Trm140 and Trm141 in fission yeasts) or three enzymes (METTL2A, METTL2B and METTL6 in mammals) are involved in its biogenesis. The rationale for the existence of multiple m3C32 methyltransferases and their substrate discrimination mechanism is hitherto unknown. Here, we revealed that both METTL2A and METTL2B are expressed in vivo. We purified human METTL2A, METTL2B, and METTL6 to high homogeneity. We successfully reconstituted m3C32 modification activity for tRNAThr by METT2A and for tRNASer(GCU) by METTL6, assisted by seryl-tRNA synthetase (SerRS) in vitro. Compared with METTL2A, METTL2B exhibited dramatically lower activity in vitro. Both G35 and t6A at position 37 (t6A37) are necessary but insufficient prerequisites for tRNAThr m3C32 formation, while the anticodon loop and the long variable arm, but not t6A37, are key determinants for tRNASer(GCU) m3C32 biogenesis, likely being recognized synergistically by METTL6 and SerRS, respectively. Finally, we proposed a mutually exclusive substrate selection model to ensure correct discrimination among multiple tRNAs by multiple m3C32 methyltransferases.

Lipoic acid alleviates L­DOPA­induced dyskinesia in 6­OHDA parkinsonian rats via anti­oxidative stress.

Levodopa (L­DOPA) is the gold standard for symptomatic treatment of Parkinson's disease (PD); however, long­term therapy is associated with the emergence of L­DOPA­induced dyskinesia (LID). Nigral dopaminergic cell loss determines the degree of drug exposure and time required for the initial onset of LID. Accumulating evidence indicates that α­lipoic acid (ALA) decreases this nigral dopaminergic cell loss. However, until now, the precise mechanisms of ALA have only been partially understood in LID. Chronic L­DOPA treatment was demonstrated to develop intense AIM scores to assess dyskinetic symptoms. Rats in the LID group were administrated twice daily with L­DOPA + benserazide for 3 weeks to induce a rat model of dyskinesia. Moreover, other 6­OHDA­lesioned rats were treatment with ALA (31.5 mg/kg or 63 mg/kg) in combination with L­DOPA treatment. Furthermore, the authors investigated the level of malondialdehyde (MDA) and glutathione (GSH) activity, as well as IBa­1, caspase­3 and poly (ADP-ribose) polymerase (PARP) in substantia nigra by the way of western blotting and immunofluorescence. ALA reduced LID in a dose­dependent manner without compromising the anti­PD effect of L­DOPA. Moreover, ALA reduced the level of MDA and upregulated the GSH activity, as well as ameliorated IBa­1 positive neurons in the substantia nigra. Finally, it was identified that ALA could reduce L­DOPA­induced cleaved­caspase­3 and PARP overexpression in the substantia nigra. Based on the present findings, ALA could be recommended as a promising disease­modifying therapy when administered with L­DOPA early in the course of PD. The exact mechanism for this action, although incompletely understood, appears to relate to anti­oxidative stress and anti­apoptosis.

Mutations in KARS cause early-onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism.

Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remains unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis, and gel filtration chromatography. Despite no alteration in the dimer-tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple-synthetase complex (MSC). Mutant LysRSs with the R477H and P505S mutations had decreased tRNALys aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.

Failure to Identify Somatic Mutations in Monozygotic Twins Discordant for Schizophrenia by Whole Exome Sequencing.

BACKGROUND: Schizophrenia (SCZ) is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations (SNVs) and somatic insertions and deletions (indels) of SCZ. METHODS: One Chinese family with a monozygotic (MZ) twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. RESULTS: One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. CONCLUSIONS: This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.

Inhibition of Glycogen Synthase Kinase-3ß (GSK-3ß) as potent therapeutic strategy to ameliorates L-dopa-induced dyskinesia in 6-OHDA parkinsonian rats.

Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3ß (GSK-3ß) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, respectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3ß played an important role in the development and expression of LID. Inhibition of GSK-3ß with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats.

Fibroblast growth factor 20 (FGF20) polymorphism is a risk factor for Parkinson's disease in Chinese population.

The etiology of Parkinson's disease (PD) is not well established. Genetic variation in fibroblast growth factor 20 (FGF20) might influence the risk of PD occurrence and development. In this study, Two DNA polymorphisms at genetic variation in FGF20, rs2720208 (C/T) and rs1721100 (C/G), were genotyped by direct sequencing in Han Chinese population, including 394 PD patients and 383 healthy controls. Statistical analyses revealed that for rs1721100 (C/G) polymorphism, there were significant differences in genotype distribution between PD and healthy-matched controls. For rs12720208 (C/T) polymorphism, there was no significant difference in genotype distribution and gender and age-related differences between PD and control group. Results in this study revealed that the rs1721100(C/G) polymorphism is a risk factor for PD in Han Chinese population, while rs12720208(C/T) polymorphism is not significantly associated with PD.

CD200-CD200R dysfunction exacerbates microglial activation and dopaminergic neurodegeneration in a rat model of Parkinson's disease.

BACKGROUND: Increasing evidence suggests that microglial activation may participate in the aetiology and pathogenesis of Parkinson's disease (PD). CD200-CD200R signalling has been shown to be critical for restraining microglial activation. We have previously shown that expression of CD200R in monocyte-derived macrophages, induced by various stimuli, is impaired in PD patients, implying an intrinsic abnormality of CD200-CD200R signalling in PD brain. Thus, further in vivo evidence is needed to elucidate the role of malfunction of CD200-CD200R signalling in the pathogenesis of PD. METHODS: 6-hydroxydopamine (6-OHDA)-lesioned rats were used as an animal model of PD. CD200R-blocking antibody (BAb) was injected into striatum to block the engagement of CD200 and CD200R. The animals were divided into three groups, which were treated with 6-OHDA/Veh (PBS), 6-OHDA/CAb (isotype control antibody) or 6-OHDA/BAb, respectively. Rotational tests and immunohistochemistry were employed to evaluate motor deficits and dopaminergic neurodegeneration in animals from each group. HPLC analysis was used to measure monoamine levels in striatum. Morphological analysis and quantification of CD11b- (or MHC II-) immunoreactive cells were performed to investigate microglial activation and possible neuroinflammation in the substantia nigra (SN). Finally, ELISA was employed to assay protein levels of proinflammatory cytokines. RESULTS: Compared with 6-OHDA/CAb or 6-OHDA/Veh groups, rats treated with 6-OHDA/BAb showed a significant increase in counts of contralateral rotation and a significant decrease in TH-immunoreactive (TH-ir) neurons in SN. A marked decrease in monoamine levels was also detected in 6-OHDA/BAb-treated rats, in comparison to 6-OHDA/Veh-treated ones. Furthermore, remarkably increased activation of microglia as well as up-regulation of proinflammatory cytokines was found concomitant with dopaminergic neurodegeneration in 6-OHDA/BAb-treated rats. CONCLUSIONS: This study shows that deficits in the CD200-CD200R system exacerbate microglial activation and dopaminergic neurodegeneration in a 6-OHDA-induced rat model of PD. Our results suggest that dysfunction of CD200-CD200R signalling may be involved in the aetiopathogenesis of PD.

Impaired CD200-CD200R-mediated microglia silencing enhances midbrain dopaminergic neurodegeneration: roles of aging, superoxide, NADPH oxidase, and p38 MAPK.

CD200-CD200R signaling holds microglia in a quiescent state. Parkinson disease (PD) neurodegeneration may be associated with impairment of CD200-CD200R-mediated microglia silencing in the substantia nigra (SN). In this study, an anti-CD200R blocking antibody (ACDR) selectively and significantly enhanced the susceptibility of dopaminergic neurons to neurotoxicity induced by rotenone (Rot) and iron (Ir) in mesencephalic neuron/glia cultures. Microglia were shown to mediate dopaminergic neurotoxicity induced by ACDR/Rot (combination of ACDR and Rot) and ACDR/Ir (combination of ACDR and Ir). ACDR significantly enhanced the microglial activation induced by Rot and Ir in neuron/glia cultures. NADPH oxidase-mediated superoxide generation was a key contributor to dopaminergic neurotoxicity induced by ACDR/Rot and ACDR/Ir. p38 MAPK contributed to NADPH oxidase activation induced by ACDR/Rot and ACDR/Ir. Interestingly, there were a decrease in CD200 expression (mRNA and protein) and an enhancement of microglial response (MHCII mRNA and ICAM-1 protein) in the rat SN with aging. ICAM-1 expression was significantly inversely correlated with CD200 expression. These results strongly indicate the participation of SN CD200-CD200R dysfunction in the etiopathogenesis of PD and provide a new insight into the molecular mechanisms underlying the involvement of aging in PD and help to elucidate the mechanisms of the combined involvement of immune/inflammatory factors, environmental substances, and aging in PD.

Four novel mutations in the GCH1 gene of Chinese patients with dopa-responsive dystonia.

Mutation detection in the guanosine triphosphate cyclohydrolase I gene (GCH1) was performed from 4 female patients with dopa-responsive dystonia (DRD). DNA sequencing revealed the presence of four novel mutations including c.2T>C(M1T), c.239G>A(S80N), c.245T>C(L82P), and IVS5+3 del AAGT. These four mutations were not found in 100 genetically unrelated healthy controls with the same ethnic background band. In all 3 childhood-onset patients, DRD started in the legs, and missense mutations were located in the coding region of GCH1. Deletion mutation in the fifth exon-intron boundary of GCH1 was detected in the adult-onset patient. Although the data presented here do not provide sufficient evidence to establish a genotype-phenotype correlation of DRD, it is important to know the clinic features and genetic defects of DRD patients, which will help prenatal diagnosis, early diagnosis, evaluate the prognosis, and facilitate causal therapy with levodopa.

Lack of association between ATP13A2 Ala746Thr variant and Parkinson's disease in Han population of mainland China.

ATP13A2 (PARK9) mutations are related to Kufor-Rakeb syndrome (KRS). We performed genetic analysis of the Ala746Thr variant in an independent cohort of the patients with PD and healthy controls from mainland China. The Ala746Thr variant was present in 1/532 (0.19%) of PD compared with 1/480 (0.21%) of healthy controls (odds ratio=0.90, 95% CI 0.06, 14.39, P=1.00). The two subjects carried the heterozygous genotype. Subset analysis in the group 50 years of age showed 0% in PD versus 0.3% in healthy controls. We did not observe a significant association between Ala746Thr and Parkinson's disease in Han Chinese population, even after stratification by age at onset. The results suggested that Ala746Thr variant was not a major susceptible factor for PD in Han Chinese people.

Malnutrition and associated factors in Chinese patients with Parkinson's disease: Results from a pilot investigation.

OBJECTIVE: This study was conducted to evaluate the prevalence of malnutrition among patients with Parkinson's disease (PD) and determine the associations between malnutrition and non-motor symptoms (NMS). METHODS: We conducted a cross-sectional assessment of 117 consecutive outpatients with PD and their respective caregivers. The participants were interviewed and assessed using various scales, including the Mini Nutritional Assessment (MNA), Non-Motor Symptoms questionnaire for Parkinson's disease (NMS quest), Mini-mental State Examination (MMSE), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Geriatric Depression Scale (GDS), and Hamilton Anxiety Scale (HAMA). We also investigated the socio-demographic characteristics of the subjects. RESULTS: The prevalence of malnutrition (MNA score < 17) was 1.71%, and 19.66% patients were at risk of malnutrition (17

Altered regulation of CD200 receptor in monocyte-derived macrophages from individuals with Parkinson's disease.

Microglia are the representative myeloid cells in the brain, and their over-activation plays an important role in the pathogenesis of Parkinson's disease (PD). Microglia activation is believed to be regulated by the CD200-CD200R signaling. As the peripheral counterpart of microglia, monocyte-derived macrophages (MDMs) share the same progenitor and antigen markers, and they have similar biological behaviors and mirror microglial function in the brain. Here, we studied CD200R expression and its regulation in MDMs from 32 PD cases, 27 age-matched old controls, and 28 young controls. We found that the basal CD200R expression is similar in MDMs from young control, old control and PD patients. However, the induction of CD200R expression in MDMs under various conditions is impaired in the old groups, especially in PD patients. There was a selective decrease in CD200R expression induced by co-culture with dying PC12 cells in MDMs from PD cases, as compared with MDMs from the age-matched controls. We also found that the inducible CD200R expression correlated inversely with the onset age of PD and to tumor necrosis factor-alpha (TNF-alpha) released from MDMs. These results suggest an intrinsic abnormality in the CD200-CD200R signaling in MDMs during aging and, especially, in PD. We speculate that in the PD brain,microglia might undergo abnormalities similar to MDMs.

Validation of the Chinese non-motor symptoms scale for Parkinson's disease: results from a Chinese pilot study.

OBJECTIVES: To evaluate a Chinese version of the Non-Motor Symptoms Scale (NMSS) in Parkinson's disease (PD) as an instrument for measuring non-motor symptoms (NMSs) in Chinese patients with Parkinson's disease. METHODS: We conducted a psychometric analysis of the Chinese version of NMSS using a cross-sectional study of 126 patients with PD. The battery also included the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS), and the Hamilton Anxiety Scale (HAMA), and was conducted by neurologists. RESULTS: There were significant correlations between the NMSS and PSQI scores (rS=0.63, P<0.001), as well as the NMSS and ESS scores (rS=0.38, P<0.001). Furthermore, significant positive correlations between NMSS and GDS, NMSS and HAMA, and NMSS and disease duration were also observed. Importantly, the sleep/fatigue index of the NMSS significantly correlated with the PSQI and ESS findings, the mood/cognition index of the NMSS significantly correlated with the GDS and HAMA findings, and the attention/memory index of the NMSS significantly correlated with the MMSE findings. CONCLUSION: The Chinese version of the NMSS can be considered a comprehensive, useful measure for NMS evaluation in Chinese PD patients.

Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation.

Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. Accumulating evidence has suggested that inflammation in the brain participates in the pathogenesis of Parkinson's disease. Luteolin, a polyphenolic compound found in foods of plant origin, belongs to the flavone subclass of flavonoids, and has been shown to possess antimutagenic, antitumorigenic, antioxidant and antiinflammatory properties. In this study, we found that luteolin concentration-dependently attenuated the lipopolysaccharide (LPS)-induced decrease in [(3)H]dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in primary mesencephalic neuron-glia cultures. Moreover, luteolin also significantly inhibited LPS-induced activation of microglia and excessive production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. Our results demonstrate that luteolin may protect dopaminergic neurons from LPS-induced injury and its efficiency in inhibiting microglia activation may underlie the mechanism.

Protective effect of isoflavones from Trifolium pratense on dopaminergic neurons.

In the present study, protective effect of five isoflavones (formononetin, daidzein, pratensein, calycosin and irilone) from Trifolium pratense on lipopolysaccharide-induced dopaminergic neurodegeneration was studied for the first time. The results showed that all five isoflavones attenuated LPS-induced decrease in dopamine uptake and the number of dopaminergic neurons in a dose-dependent manner in rat mesencephalic neuron-glia cultures. Moreover, they also significantly inhibited LPS-induced activation of microglia and production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. In addition, the rank order of protective potency of five isoflavones was: pratensein>daidzein>calycosin>formononetin>irilone. This study suggested that all five isoflavones protected dopaminergic neurons against LPS-induced injury through inhibition of microglia activation and proinflammatory factors generation.

Neuroprotective effects of PACAP27 in mice model of Parkinson's disease involved in the modulation of K(ATP) subunits and D2 receptors in the striatum.

Pituitary adenylate cyclase activating polypeptide (PACAP) exhibits a protective effect against neural injury in vitro and in vivo. However, it has not been reported whether peripheral intravenous administration of PACAP could confer benefits in animal models of Parkinson's disease (PD). Furthermore, the underlying molecular mechanisms responsible for these effects are poorly understood. In the present experiments, we determined the effects and mechanism of action of intravenously administered PACAP27 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Our results indicate that intravenous injection of PACAP27 offers neuroprotective effects in the MPTP-induced PD mouse model which may not be directly associated with the expression levels of the monoamine transporters. However, this effect may be correlated with its ability to selectively regulate not only K(ATP) subunits, but D2 receptors in the striatum. Our findings suggest that the benefit of PACAP may accompany with changes not only in dopaminergic neurotransmission, but also in cholinergic neurotransmission that are relatively associated with the K(ATP) subunits and D2 receptors in the striatum.

CD200-CD200R regulation of microglia activation in the pathogenesis of Parkinson's disease.

The role of CD200-CD200R signaling in immune regulation of the central nervous system has become a popular field of research in recent years. Many studies have shown that there is a close correlation between CD200-CD200R, microglia activation, and Parkinson's disease (PD). This review discusses the above relationship, highlighting (1) the gene mapping and molecular structure of CD200 and CD200R, (2) the distribution and expression of CD200 and CD200R in the nervous system, (3) the effect of CD200-CD200R signaling on microglia activation, and (4) the role of microglia activation in the pathogenesis and progression of PD. Finally, we discuss the status of current studies on the regulation of microglia activation in PD and strongly suggest that it is very promising to regulate microglia activation in PD via targeting CD200-CD200R signaling pathways.