The direct and indirect effects of α-synuclein on microtubule stability in the pathogenesis of Parkinson's disease.

Despite decades of research, the mechanism of Parkinson's disease pathogenesis remains unclear. Studies have focused heavily on the protein α-synuclein, which is the primary component of Lewy bodies, the pathologic inclusions that are the hallmark of Parkinson's on the cellular level. While the roles of α-synuclein in causing mitochondrial dysfunction and disruptions to the proteasomal system have been well documented, recently, its role in effecting microtubule dynamics has been investigated as a potential source of pathogenicity. Here, we evaluate the evidence for and against the role of α-synuclein in destabilizing microtubules, causing axonal transport deficits and eventually neurodegeneration. We present evidence for a model where α-synuclein has both a direct and indirect effect on microtubule stability. Directly, it may act as a microtubule-associated protein, binding to microtubules and directly effecting their dynamics. Indirectly, it may promote the hyperphosphorylation of the microtubule stabilizing protein, tau, leading to tau aggregation with other microtubule stabilizing proteins, hence indirectly causing microtubule destabilization. This model provides insights into the function of α-synuclein and tau in Parkinson's disease pathogenesis and raises the possibility that this role that may also be conserved in Alzheimer's disease.

CD24 expression does not affect dopamine neuronal survival in a mouse model of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative condition that is characterised by the loss of specific populations of neurons in the brain. The mechanisms underlying this selective cell death are unknown but by using laser capture microdissection, the glycoprotein, CD24 has been identified as a potential marker of the populations of cells that are affected in PD. Using in situ hybridization and immunohistochemistry on sections of mouse brain, we confirmed that CD24 is robustly expressed by many of these subsets of cells. To determine if CD24 may have a functional role in PD, we modelled the dopamine cell loss of PD in Cd24 mutant mice using striatal delivery of the neurotoxin 6-OHDA. We found that Cd24 mutant mice have an anatomically normal dopamine system and that this glycoprotein does not modulate the lesion effects of 6-OHDA delivered into the striatum. We then undertook in situ hybridization studies on sections of human brain and found-as in the mouse brain-that CD24 is expressed by many of the subsets of the cells that are vulnerable in PD, but not those of the midbrain dopamine system. Finally, we sought to determine if CD24 is required for the neuroprotective effect of Glial cell-derived neurotrophic factor (GDNF) on the dopaminergic nigrostriatal pathway. Our results indicate that in the absence of CD24, there is a reduction in the protective effects of GDNF on the dopaminergic fibres in the striatum, but no difference in the survival of the cell bodies in the midbrain. While we found no obvious role for CD24 in the normal development and maintenance of the dopaminergic nigrostriatal system in mice, it may have a role in mediating the neuroprotective aspects of GDNF in this system.

Drug use, health and social outcomes of hard-to-treat heroin addicts receiving supervised injectable opiate treatment: secondary outcomes from the Randomized Injectable Opioid Treatment Trial (RIOTT).

AIMS: The Randomized Injectable Opioid Treatment Trial (RIOTT) compared supervised injectable heroin (SIH) and supervised injectable methadone (SIM) with optimized oral methadone (OOM) (ISRCTN0133807). Heroin addicts (previously unresponsive to treatment) made significant reductions in street heroin use at 6 months when treated with SIH. We now examine secondary outcomes. DESIGN: Multi-site randomized controlled trial (RCT) comparing SIH versus OOM and SIM versus OOM. SETTING: Three supervised injectable opiate clinics in England. PARTICIPANTS: Chronic refractory heroin addicts continuing to inject street heroin virtually daily despite oral substitution treatment (n = 127), randomized to either SIH(n = 43), SIM(n = 42) or OOM(n = 42). All received high levels of medical and psychosocial support. SECONDARY OUTCOMES: wider drug use, crime, health and social functioning at 6 months. FINDINGS: At 6 months, no significant differences were found between treatment groups in wider drug use (crack/cocaine, benzodiazepines, alcohol), physical and mental health (SF-36) or social functioning. Within each treatment group, significant reductions were observed in crime [SIH = odds ratio (OR) 0.05; P < 0.001; SIM = OR 0.11; P = 0.002; OOM = OR 0.11; P = 0.003] and money spent per week on illicit drugs (SIH = mean change £-289.43; P < 0.001; SIM = mean change £-183.41; P < 0.001; OOM = mean change £-162.80; P < 0.001), with SIH significantly more likely to have reduced money spent on illicit drugs versus OOM (mean difference £-92.04; P < 0.001). Significant improvements were seen in physical health for SIH and SIM (SIH = mean change 3.97; P = 0.008; SIM = mean change 4.73; P = 0.002) and mental health for OOM (mean change 6.04; P = 0.013). CONCLUSIONS: Supervised injectable heroin treatment and supervised injectable methadone treatment showed no clearly identified benefit over optimized oral methadone in terms of wider drug use, crime, physical and mental health within a 6-month period, despite reducing street heroin use to a greater extent. However, all interventions were associated with improvements in these outcomes.

Supervised injectable heroin or injectable methadone versus optimised oral methadone as treatment for chronic heroin addicts in England after persistent failure in orthodox treatment (RIOTT): a randomised trial.

BACKGROUND: Some heroin addicts persistently fail to benefit from conventional treatments. We aimed to compare the effectiveness of supervised injectable treatment with medicinal heroin (diamorphine or diacetylmorphine) or supervised injectable methadone versus optimised oral methadone for chronic heroin addiction. METHODS: In this multisite, open-label, randomised controlled trial, we enrolled chronic heroin addicts who were receiving conventional oral treatment (>or=6 months), but continued to inject street heroin regularly (>or=50% of days in preceding 3 months). Randomisation by minimisation was used to assign patients to receive supervised injectable methadone, supervised injectable heroin, or optimised oral methadone. Treatment was provided for 26 weeks in three supervised injecting clinics in England. Primary outcome was 50% or more of negative specimens for street heroin on weekly urinalysis during weeks 14-26. Primary analysis was by intention to treat; data were adjusted for centre, regular crack use at baseline, and treatment with optimised oral methadone at baseline. Percentages were calculated with Rubin's rules and were then used to estimate numbers of patients in the multiple imputed samples. This study is registered, ISRCTN01338071. FINDINGS: Of 301 patients screened, 127 were enrolled and randomly allocated to receive injectable methadone (n=42 patients), injectable heroin (n=43), or oral methadone (n=42); all patients were included in the primary analysis. At 26 weeks, 80% (n=101) patients remained in assigned treatment: 81% (n=34) on injectable methadone, 88% (n=38) on injectable heroin, and 69% (n=29) on oral methadone. Patients on injectable heroin were significantly more likely to have achieved the primary outcome (72% [n=31]) than were those on oral methadone (27% [n=11], OR 7.42, 95% CI 2.69-20.46, p<0.0001; adjusted: 66% [n=28] vs 19% [n=8], 8.17, 2.88-23.16, p<0.0001), with number needed to treat of 2.17 (95% CI 1.60-3.97). For injectable methadone (39% [n=16]; adjusted: 30% [n=14]) versus oral methadone, the difference was not significant (OR 1.74, 95% CI 0.66-4.60, p=0.264; adjusted: 1.79, 0.67-4.82, p=0.249). For injectable heroin versus injectable methadone, a significant difference was recorded (4.26, 1.63-11.14, p=0.003; adjusted: 4.57, 1.71-12.19, p=0.002), but the study was not powered for this comparison. Differences were evident within the first 6 weeks of treatment. INTERPRETATION: Treatment with supervised injectable heroin leads to significantly lower use of street heroin than does supervised injectable methadone or optimised oral methadone. UK Government proposals should be rolled out to support the positive response that can be achieved with heroin maintenance treatment for previously unresponsive chronic heroin addicts. FUNDING: Community Fund (Big Lottery) Research section, through Action on Addiction.

Prescribing heroin.

Recent UK guidelines support the prescription of injectable heroin and methadone for opiate dependence, but many doctors disagree. Heroin has been prescribed in England for almost a hundred years, and the "British system" was once the subject of international curiosity. Since 1965, a prescriber licensing system has led to a great reduction in the proportion of opiate addicts treated with heroin. Recent trials in Switzerland and the Netherlands have prompted a review of British practice. It will probably remain somewhat different from continental practice, particularly with respect to long-term supervised injecting, but without adequate funding it may disappear altogether.

Heroin prescription for heroin addiction - an English view.

Heroin has been prescribed in England for the treatment of heroin addiction for almost 100 years. For many years, England was almost the only country where this occurred, and the British system was consequently the subject of international curiosity. In spite of this long history, very little research has been carried out locally, and until recently, there were no guidelines as to best practice. In 1965, it was decided that only doctors with a Home Office license could prescribe heroin. Since that time, the proportion of opiate addicts treated with heroin has greatly diminished, as has the number of doctors willing to prescribe. One doctor in particular remained an enthusiastic proponent of heroin prescription. His claims impressed some Swiss clinicians, who proceeded to establish a multicentre trial in Switzerland. This was followed by a similar trial in the Netherlands. These trials apparently indicated that a proportion of treatment-resistant opiate addicts could respond well to heroin, although the researchers' conclusions have been disputed. The National Treatment Agency in England is now developing guidelines for good practice based on this new information and is planning to set up some pilot sites. It is likely that practise in England will remain somewhat different from continental practice, particularly with respect to long-term supervised injecting. It is unclear how much funding will be released to support heroin prescription. Without adequate funding, it is likely to disappear.

The prescription of dexamphetamine to patients with schizophrenia and amphetamine dependence.

Patients with a severe mental illness such as schizophrenia have significant rates of concurrent amphetamine use. Such dual diagnosis patients have been shown to have poorer treatment outcomes. Often, they do not comply with treatment plans and have frequent episodes of hospitalization. There is growing evidence for the role of prescribed dexamphetamine in the treatment of amphetamine dependence. The prescription of dexamphetamine to patients with schizophrenia and amphetamine dependence has not been previously reported. Eight schizophrenic patients are described to whom dexamphetamine has been prescribed, with information being extracted retrospectively from case notes. In four out of eight cases, the prescription of dexamphetamine led to apparently good progress both in terms of substance misuse and psychiatric health. In two cases, progress was more equivocal, but appeared to produce some benefit. Two cases could be judged as treatment failures, but the condition and situation of the patients were not worse at the end of treatment than at the beginning. Compliance with neuroleptics increased in most cases. No patients exhibited exacerbation of psychosis as a result of treatment. The rate of outcome success is satisfactory when consideration is given to the difficult nature of this patient group, and their previous failure to respond to intensive treatment. It is argued that benefits may be gained from increased compliance with psychiatric treatment in patients prescribed amphetamine, and that this may outweigh possible risks. However, any conclusions are tentative in view of the nature of this study. A small open-label prospective study is recommended.

Survey of doctors prescribing diamorphine (heroin) to opiate-dependent drug users in the United Kingdom.

AIM: To determine the scale and practice of diamorphine (heroin) prescribing for opiate dependence in the United Kingdom in 2000. DESIGN: Postal survey. SETTING: England, Scotland and Wales. PARTICIPANTS: One hundred and eleven of the 164 doctors in the United Kingdom on the Home Office record as holding a licence to prescribe diamorphine (response rate 68%), and 59 of the 108 doctors in the United Kingdom eligible to hold a licence (working in drug clinics), but not doing so (response rate 54%). MEASUREMENTS: The characteristics of doctors (a) holding a licence and (b) currently prescribing; the number of opiate users receiving a prescription; current treatment delivery, clinical criteria for patient eligibility; and reasons for prescribing or not prescribing diamorphine. FINDINGS: Seventy of the 111 doctors actually held a licence. While the majority were consultant psychiatrists, five were general practitioners. Forty-six were currently prescribing to 448 patients. The majority of prescribers reported that they had not initiated a prescription for diamorphine but had inherited patients already receiving such a prescription. Most of those who prescribed considered that in selected cases it could produce clinical and social improvement. There were great variations in clinical criteria for patient eligibility, prescribing practice, daily dose prescribed (range 5-1500 mg) and the daily dose-equivalent of 100 mg methadone (range 50-900 mg). Many respondents cited lack of appropriate resources as a reason for not prescribing to more patients. Reasons for non-prescribing varied from lack of resources to little evidence of its effectiveness. CONCLUSIONS: The prescribing of diamorphine to opiate dependent drug users remains rare in the United Kingdom. Not all eligible doctors seek a licence to prescribe, and not all those with licences actually prescribe it. There is no clear consensus on who should be treated with diamorphine and in what way.