No abstract

Background: The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence.We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. Methods: We did a Bayesian-framework, multipletreatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. Findings: We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from 20·09 for the best drug (haloperidol) to 20·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to 21·30 192 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to 20·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in metaregressions and sensitivit...

Identification of mutations that cause rare familial forms of Parkinson's disease (PD) and subsequent studies of genetic risk factors for sporadic PD have led to an improved understanding of the pathological mechanisms that may cause nonfamilial PD. In particular, genetic and pathological studies strongly suggest that alpha-synuclein, albeit very rarely mutated in PD patients, plays a critical role in the vast majority of individuals with the sporadic form of the disease. We have extensively characterized a mouse model over-expressing full-length, human, wild-type alpha-synuclein under the Thy-1 promoter. We have also shown that this model reproduces many features of sporadic PD, including progressive changes in dopamine release and striatal content, alphasynuclein pathology, deficits in motor and nonmotor functions that are affected in pre-manifest and manifest phases of PD, inflammation, and biochemical and molecular changes similar to those observed in PD. Preclinical studies have already demonstrated improvement with promising new drugs in this model, which provides an opportunity to test novel neuroprotective strategies during different phases of the disorder using endpoint measures with high power to detect drug effects.

Overexpression or mutation of α-synuclein (α-Syn), a protein associated with presynaptic vesicles, causes familial forms of Parkinson’s disease in humans and is also associated with sporadic forms of the disease. We used in vivo microdialysis, tissue content analysis, behavioral assessment, and whole-cell patch clamp recordings from striatal medium-sized spiny neurons (MSSNs) in slices to examine dopamine transmission and dopaminergic modulation of corticostriatal synaptic function in mice overexpressing human wild-type α-Syn under the Thy1 promoter (α-Syn mice). Tonic striatal extracellular dopamine and 3-methoxytyramine levels were elevated in α-Syn mice at 6 months of age, prior to any reduction in total striatal tissue content, and were accompanied by an increase in open-field activity. Dopamine clearance and amphetamine-induced dopamine efflux were unchanged. The frequency of MSSN spontaneous excitatory postsynaptic currents (sEPSCs) was lower in α-Syn mice. Amphetamine reduced sEPSC frequency in wild types (WTs) but produced no effect in α-Syn mice. Furthermore, whereas quinpirole reduced and sulpiride increased sEPSC frequency in WT mice, they produced the opposite effects in α-Syn mice. These observations indicate that overexpression of α-Syn alters dopamine efflux and D2 receptor modulation of corticostriatal glutamate release at a young age. At 14 months of age, the α-Syn mice presented with significantly lower striatal tissue dopamine and tyrosine hydroxylase content relative to WT littermates, accompanied by an L-DOPA-reversible sensory motor deficit. Together, these data further validate this transgenic mouse line as a slowly progressing model of Parkinson’s disease and provide evidence for early dopamine synaptic dysfunction prior to loss of striatal dopamine.

Parkinson’s disease (PD) is characterized by widespread alpha-synuclein pathology and neuronal loss, primarily of the nigrostriatal dopaminergic neurons. Inflammation has been implicated in PD, and alpha-synuclein can initiate microglial activation; however, the kinetics and distribution of inflammatory responses to alpha-synuclein overexpression in vivo are not well understood. We have examined the regional and temporal pattern of microglial activation and pro-inflammatory cytokine production in mice over-expressing wild-type human alpha-synuclein driven by the Thy1-promoter (Thy1-aSyn mice). Increased number of activated microglia, and increased levels of TNF-α mRNA and protein were first detected in the striatum (1 month of age) and later in the substantia nigra (5–6 months), but not cerebral cortex or cerebellum; in contrast, IL-1β and TGFβ remained unchanged in striatum and substantia nigra at all ages examined. Microglial activation persisted up to 14 months of age in these regions and only minimal increases were observed in other regions at this later age. Increased concentrations of serum TNF-α were observed at 5–6 months, but not 1 month of age. The expression of toll-like receptors (TLR) 1, TLR 4 and TLR 8, which are possible mediators of microglial activation, was increased at 5–6 months in the substantia nigra but not in the cerebral cortex, and TLR 2 was increased in the substantia nigra at 14 months of age. With the exception of a slight increase in the striatum of 14 months old Thy1-aSyn mice, MHCII staining was not detected in the regions and ages examined. Similarly, peripheral CD4 and CD8-postive T cells were increased in the blood but only at 22 months of age, suggesting later involvement of the adaptive immune response. These data indicate that, despite the presence of high levels of alpha-synuclein in other brain regions, alpha-synuclein overexpression caused a selective early inflammatory response in regions containing the axon terminals and cell bodies of the nigrostriatal pathway. Our results suggest that specific factors, possibly involving a regionally and temporally selective increase in TLRs, mediate alpha-synuclein-induced inflammatory responses in the SN, and may play a role in the selective vulnerability of nigrostriatal dopaminergic neurons in PD.

Hemoglobin is the oxygen carrier in vertebrate blood erythrocytes. Here we report that hemoglobin chains are expressed in mammalian brain neurons and are regulated by a mitochondrial toxin. Transcriptome analyses of laser-capture microdissected nigral dopaminergic neurons in rats and striatal neurons in mice revealed the presence of hemoglobin α, adult chain 2 (Hba-a2) and hemoglobin β (Hbb) transcripts, whereas other erythroid markers were not detected. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis confirmed the expression of Hba-a2 and Hbb in nigral dopaminergic neurons, striatal γ-aminobutyric acid (GABA)ergic neurons, and cortical pyramidal neurons in rats. Combined in situ hybridization histochemistry and immunohistochemistry with the neuronal marker neuronal nuclear antigen (NeuN) in rat brain further confirmed the presence of hemoglobin mRNAs in neurons. Immunohistochemistry identified hemoglobin α- and β-chains in both rat and human brains, and hemoglobin proteins were detected by Western blotting in whole rat brain tissue as well as in cultures of mesencephalic neurons, further excluding the possibility of blood contamination. Systemic administration of the mitochondrial inhibitor rotenone (2 mg/kg/d, 7d, s.c.) induced a marked decrease in Hba-a2 and Hbb but not neuroglobin or cytoglobin mRNA in transcriptome analyses of nigral dopaminergic neurons. Quantitative RT-PCR confirmed the transcriptional downregulation of Hba-a2 and Hbb in nigral, striatal, and cortical neurons. Thus, hemoglobin chains are expressed in neurons and are regulated by treatments that affect mitochondria, opening up the possibility that they may play a novel role in neuronal function and response to injury.

No abstract

The obligate biotrophic pathogen Plasmodiophora brassicae causes clubroot disease in Arabidopsis thaliana, which is characterized by large root galls. Salicylic acid (SA) production is a defence response in plants, and its methyl ester is involved in systemic signalling. Plasmodiophora brassicae seems to suppress plant defence reactions, but information on how this is achieved is scarce. Here, we profile the changes in SA metabolism during Arabidopsis clubroot disease. The accumulation of SA and the emission of methylated SA (methyl salicylate, MeSA) were observed in P. brassicae-infected Arabidopsis 28 days after inoculation. There is evidence that MeSA is transported from infected roots to the upper plant. Analysis of the mutant Atbsmt1, deficient in the methylation of SA, indicated that the Arabidopsis SA methyltransferase was not responsible for alterations in clubroot symptoms. We found that P. brassicae possesses a methyltransferase (PbBSMT) with homology to plant methyltransferases. The PbBSMT gene is maximally transcribed when SA production is highest. By heterologous expression and enzymatic analyses, we showed that PbBSMT can methylate SA, benzoic and anthranilic acids.