Journal of Neuroimmune Pharmacology最新文献

Smartphone-based interventions are increasingly used to support self-monitoring, self-management, and treatment and medication compliance in order to improve overall functioning and well-being. In attempting to develop a smartphone application (S-Health) that assists heroin-dependent patients in recovery, a series of focus groups (72 patients, 22 providers) were conducted in China, Taiwan, and the USA to obtain their perspectives on its acceptance and potential adoption. Data were analyzed according to the Diffusion of Innovation (DOI) theory of characteristics important to the adoption of innovation. Important to Relative Advantage, USA participants cited S-Health's potential ability to overcome logistical barriers, while those in China and Taiwan valued its potential to supplement currently limited services. In terms of Compatibility, participants across sites reported recovery needs and goals that such an application could be helpful in supporting; however, its utility during strong craving was questioned in China and Taiwan. Important factors relevant to Complexity included concerns about smartphone access and familiarity, individualization of content, and particularly in China and Taiwan, participants wanted assurance of privacy and security. The study results suggest a general acceptance, but also indicate cultural variations in access to therapeutic and other social support systems, legal repercussions of substance use, societal perceptions of addiction, and the role of family and other social support in recovery. Taking these factors into consideration is likely to increase diffusion as well as effectiveness of these smartphone-based interventions.

Quitting smoking significantly reduces the risk of tobacco-related morbidity and mortality, yet there is a high rate of relapse amongst smokers who try to quit. Phenotypic biomarkers have the potential to improve smoking cessation outcomes by identifying the best available treatment for an individual smoker. In this review, we introduce the nicotine metabolite ratio (NMR) as a reliable and stable phenotypic measure of nicotine metabolism that can guide smoking cessation treatment among smokers who wish to quit. We address how the NMR accounts for sources of variation in nicotine metabolism including genotype and other biological and environmental factors such as estrogen levels, alcohol use, body mass index, or menthol exposure. Then, we highlight clinical trials that validate the NMR as a biomarker to predict therapeutic response to different pharmacotherapies for smoking cessation. Current evidence supports the use of nicotine replacement therapy for slow metabolizers, and non-nicotine treatments such as varenicline for normal metabolizers. Finally, we discuss future research directions to elucidate mechanisms underlying NMR associations with treatment response, and facilitate the implementation of the NMR as biomarker in clinical practice to guide smoking cessation.

Addictive stimulant drugs, such as cocaine, are known to increase the risk of exposure to HIV-1 infection and hence predispose towards the development of AIDS. Previous findings suggested that the combined effect of chronic cocaine administration and HIV-1 infection enhances cell death. Neuronal survival is highly dependent on the health of mitochondria providing a rationale for assessing mitochondrial integrity and functionality following cocaine treatment, either alone or in combination with the HIV-1 viral protein Tat, by monitoring ATP release and mitochondrial membrane potential (ΔΨm). Our results indicate that exposing human and rat primary hippocampal neurons to cocaine and HIV-1 Tat synergistically decreased both mitochondrial membrane potential and ATP production. Additionally, since previous studies suggested HIV-1 infection alters autophagy in the CNS, we investigated how HIV-1 Tat and cocaine affect autophagy in neurons. The results indicated that Tat induces an increase in LC3-II levels and the formation of Parkin-ring-like structures surrounding damaged mitochondria, indicating the possible involvement of the Parkin/PINK1/DJ-1 (PPD) complex in neuronal degeneration. The importance of mitochondrial damage is also indicated by reductions in mitochondrial membrane potential and ATP content induced by HIV-1 Tat and cocaine.

While the specific trigger of Parkinson Disease (PD) in most patients is unknown, considerable evidence suggests that the neuroinflammatory response makes an essential contribution to the neurodegenerative process. Drugs targeting metabotropic glutamate receptors (mGlu receptors), 7 Transmembrane (7TM) spanning/G protein coupled receptors that bind glutamate, are emerging as therapeutic targets for PD and may have anti-inflammatory properties. ADX88178 is novel potent, selective, and brain-penetrant positive allosteric modulator of the mGlu4 which is under evaluation for treatment of PD and other neurological disorders. We used microglia cultured from mouse brain to determine if ADX88178 had direct effects on the inflammatory responses of these cells. We studied both microglia from wild type and Grm4 knock out mice. We found that activation of mGlu4 with ADX88178 attenuated LPS-induced inflammation in primary microglia, leading to a decrease in the expression of TNFα, MHCII, and iNOS, markers of pro-inflammatory responses. These effects were absent in microglia from mice lacking mGlu4. These results demonstrate a cell-autonomous anti-inflammatory effect of ADX88178 mediated mGlu4 activation on microglia, and suggest that this drug or similar activators or potentiators of mGlu4 may have disease-modifying as well as symptomatic effects in PD and other brain disorders with an inflammatory component.

Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson's disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP(+)-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.