RESUMO
BACKGROUND AND PURPOSE: Chronic inflammation may play a role in the pathogenesis of Parkinson's disease (PD). Noradrenaline is an endogenous neurotransmitter with anti-inflammatory properties. In the present investigation, we assessed the immunomodulatory and neuroprotective efficacy of pharmacologically targeting the CNS noradrenergic system in a rat model of PD. EXPERIMENTAL APPROACH: The impact of treatment with the ß2 -adrenoceptor agonists clenbuterol and formoterol was assessed in the intranigral LPS rat model of PD. The immunomodulatory potential of formoterol to influence the CNS response to systemic inflammation was also assessed. KEY RESULTS: LPS-induced deficits in motor function (akinesia and forelimb-use asymmetry) and nigrostriatal dopamine loss were rescued by both agents. Treatment with the noradrenaline reuptake inhibitor atomoxetine reduced striatal dopamine loss and motor deficits following intranigral LPS injection. Co-treatment with the ß2 -adrenoceptor antagonist ICI 118,551 attenuated the protective effects of atomoxetine. Systemic LPS challenge exacerbated reactive microgliosis, IL-1ß production, dopamine cell loss in the substantia nigra, nerve terminal degeneration in the striatum, and associated motor impairments in animals that previously received intranigral LPS. This exacerbation was attenuated by formoterol treatment. CONCLUSION AND IMPLICATIONS: The results indicate that pharmacologically targeting ß2 -adrenoceptors has the propensity to regulate the neuroinflammatory phenotype in vivo and may be a potential neuroprotective strategy where inflammation contributes to the progression of dopaminergic neurodegeneration. In accordance with this, clinical agents such as ß2 -adrenoceptor agonists may prove useful as immunomodulatory agents in the treatment of neurodegenerative conditions associated with brain inflammation.
Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Anti-Inflamatórios/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Animais , Cloridrato de Atomoxetina/farmacologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Clembuterol/farmacologia , Modelos Animais de Doenças , Fumarato de Formoterol/farmacologia , Lipopolissacarídeos , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Atividade Motora/efeitos dos fármacos , Degeneração Neural , Neurônios/metabolismo , Neurônios/patologia , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologia , Ratos Wistar , Receptores Adrenérgicos beta 2/metabolismoRESUMO
BACKGROUND: Fine scale geospatial analysis of HIV infection patterns can be used to facilitate geographically targeted interventions. Our objective was to use the geospatial technology to map age and time standardized HIV incidence rates over a period of 10 years to identify communities at high risk of HIV in the greater Durban area. METHODS: HIV incidence rates from 7557 South African women enrolled in five community-based HIV prevention trials (2002-2012) were mapped using participant household global positioning system (GPS) coordinates. Age and period standardized HIV incidence rates were calculated for 43 recruitment clusters across greater Durban. Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and clustering of new HIV infections in recruitment communities. RESULTS: The total person-time in the cohort was 9093.93 years and 613 seroconversions were observed. The overall crude HIV incidence rate across all communities was 6·74 per 100PY (95% CI: 6·22-7·30). 95% of the clusters had HIV incidence rates greater than 3 per 100PY. The CAR analysis identified six communities with significantly high HIV incidence. Estimated relative risks for these clusters ranged from 1.34 to 1.70. Consistent with these results, age standardized HIV incidence rates were also highest in these clusters and estimated to be 10 or more per 100 PY. Compared to women 35+ years old younger women were more likely to reside in the highest incidence areas (aOR: 1·51, 95% CI: 1·06-2·15; aOR: 1.59, 95% CI: 1·19-2·14 and aOR: 1·62, 95% CI: 1·2-2·18 for < 20, 20-24, 25-29 years old respectively). Partnership factors (2+ sex partners and being unmarried/not cohabiting) were also more common in the highest incidence clusters (aOR 1.48, 95% CI: 1.25-1.75 and aOR 1.54, 95% CI: 1.28-1.84 respectively). CONCLUSION: Fine geospatial analysis showed a continuous, unrelenting, hyper HIV epidemic in most of the greater Durban region with six communities characterised by particularly high levels of HIV incidence. The results motivate for comprehensive community-based HIV prevention approaches including expanded access to PrEP. In addition, a higher concentration of HIV related services is required in the highest risk communities to effectively reach the most vulnerable populations.
Assuntos
Infecções por HIV/epidemiologia , Adulto , Análise por Conglomerados , Estudos de Coortes , Feminino , Humanos , Incidência , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , África do Sul/epidemiologia , Adulto JovemRESUMO
OBJECTIVES: Clenbuterol is a brain penetrant ß2-adrenoceptor agonist with anti-inflammatory and putative neuroprotective properties. In the present investigation, the effect of clenbuterol was assessed in a rat model of acute brain injury induced by intra-striatal administration of the pro-inflammatory cytokine IL-1ß. METHODS: Clenbuterol (0.5 mg/kg; i.p.) was administered one hour prior to stereotactically delivered IL-1ß (100 ng) into the striatum. Four hours postinjection, rats were anesthetized, blood samples were collected for circulating cytokine and chemokine analysis, and the ipsilateral striatum and liver tissue were harvested for mRNA expression analysis of target genes. RESULTS: Intrastriatal IL-1ß provoked an inflammatory response with increased expression of IL-1ß and the pro-inflammatory cytokine TNF-α. TNF-α expression was also increased in the liver and circulating concentrations of the chemokine cytokine-induced neutrophil chemoattractant 1 (CINC-1) were raised in response to intrastriatal IL-1ß administration. The striatal response was accompanied by NFκB activation and 24 hours postinjection, increased immunoreactivity of the neutrophil marker MBS-2, indicative of cell infiltration and increased TUNEL staining, a cell marker of apoptosis. Treatment with clenbuterol attenuated all IL-1ß-induced changes in the striatum including MBS-2 immunoreactivity and TUNEL + staining. Clenbuterol also attenuated IL-1ß-induced expression of TNF-α in the liver and the increase in circulating CINC-1 concentrations. CONCLUSIONS: The results provide evidence that clenbuterol elicits anti-inflammatory effects, suppresses the peripheral acute phase response and reduces the infiltration of neutrophils and apoptotic response to acute IL-1ß-induced brain injury. Suppression of both the central and peripheral response following clenbuterol administration may contribute to its protective properties following brain injury.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Lesões Encefálicas , Clembuterol/farmacologia , Interleucina-1beta/toxicidade , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Animais , Lesões Encefálicas/induzido quimicamente , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Lesões Encefálicas/prevenção & controle , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Neutrófilos/patologia , Ratos , Ratos WistarRESUMO
The impact of treatment with the noradrenaline (NA) re-uptake inhibitor atomoxetine and the α2-adrenoceptor (AR) antagonist idazoxan in an animal model of Parkinson's disease (PD) was assessed. Concurrent systemic treatment with atomoxetine and idazoxan, a combination which serves to enhance the extra-synaptic availability of NA, exerts anti-inflammatory and neuroprotective effects following delivery of an inflammatory stimulus, the bacterial endotoxin, lipopolysaccharide (LPS) into the substantia nigra. Lesion-induced deficits in motor function (akinesia, forelimb-use asymmetry) and striatal dopamine (DA) loss were rescued to varying degrees depending on the treatment. Treatment with atomoxetine following LPS-induced lesion to the substantia nigra, yielded a robust anti-inflammatory effect, suppressing microglial activation and expression of the pro-inflammatory cytokine TNF-α whilst increasing the expression of neurotrophic factors. Furthermore atomoxetine treatment prevented loss of tyrosine hydroxylase (TH) positive nigral dopaminergic neurons and resulted in functional improvements in motor behaviours. Atomoxetine alone was sufficient to achieve most of the observed effects. In combination with idazoxan, an additional improvement in the impairment of contralateral limb use 7â¯days post lesion and a reduction in amphetamine-mediated rotational asymmetry 14â¯days post-lesion was observed, compared to atomoxetine or idazoxan treatments alone. The results indicate that increases in central NA tone has the propensity to regulate the neuroinflammatory phenotype in vivo and may act as an endogenous neuroprotective mechanism where inflammation contributes to the progression of DA loss. In accordance with this, the clinical use of agents such as NA re-uptake inhibitors and α2-AR antagonists may prove useful in enhancing the endogenous neuroimmunomodulatory potential of NA in conditions associated with brain inflammation.
Assuntos
Cloridrato de Atomoxetina/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Idazoxano/farmacologia , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/uso terapêutico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Cloridrato de Atomoxetina/uso terapêutico , Encéfalo/metabolismo , Encéfalo/patologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Idazoxano/uso terapêutico , Lipopolissacarídeos , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologia , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
In this study we examined the impact of systemic treatment with the long-acting brain penetrant ß2-adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain. Clenbuterol decreased NFκB activity (p65 DNA binding) in nuclear extracts prepared from rat cortex and hippocampus for up to 8h following a single treatment. This was accompanied by increased expression of IκBα mRNA and protein. The temporal increase in IκB protein expression paralleled the suppression of NFκB activity, suggesting that IκBα mediates the suppression NFκB activity observed. These actions of clenbuterol were prevented by pre-treatment with the non-selective ß-adrenoceptor antagonist propranolol, the ß2-adrenoceptor antagonist ICI-118,551, but not the ß1-adrenoceptor antagonist metoprolol, suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the ß2-adrenoceptor. In addition, the actions of clenbuterol were mimicked by systemic administration of another highly selective long-acting ß2-adrenoceptor agonist formoterol. As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus. In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide (LPS). In tandem, clenbuterol blocked expression of the NFκB-inducible genes TNF-α and ICAM-1 following LPS administration. Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that ß2-adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation-related neurodegeneration.