Li W.,Diana Helis Henry Medical Research Foundation |
Doyon W.M.,Baylor College of Medicine |
Dani J.A.,Baylor College of Medicine
Biochemical Pharmacology | Year: 2011
Altered functional interactions among midbrain dopamine (DA) neurons contribute to the reinforcing properties of environmental stimuli and addictive drugs. To examine correlations among DA neurons, acute nicotine was administrated to rats via an intraperitoneal catheter and unit activity was measured using multi-tetrode in vivo recordings. Nicotine administration enhanced the correlated activity of simultaneously recorded DA neurons from the ventral tegmental area (VTA). The strength of the correlations between DA neuron pairs, as measured by cross covariance among two spike trains, showed dynamic changes over time. Nicotine produced a gradual rise in firing rate and burst activity that reached a stable plateau approximately 20 min after the intraperitoneal nicotine infusion. Shortly after that time the cross correlations measured using 5-ms bins increased significantly above baseline. In addition, nicotine increased the firing rates of DA neurons in the posterior VTA more than in the anterior VTA. Unlike nicotine, eticlopride administration also boosted DA neuron firing activity but did not enhance synchronization, indicating that the cross correlations induced by nicotine were not due to a non-specific increase in firing rate. The overall results show that nicotine induces nearly synchronous firing by a subset of DA neurons, and those changes in correlative firing will enhance the DA signal that contributes to nicotine-induced behavioral reinforcement. © 2011 Elsevier Inc.
Pan T.,Diana Helis Henry Medical Research Foundation |
Pan T.,Baylor College of Medicine |
Li X.,University of Texas M. D. Anderson Cancer Center |
Jankovic J.,Baylor College of Medicine
International Journal of Cancer | Year: 2011
Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of melanin-positive, dopaminergic neurons in the substantia nigra. Although there is convincing epidemiologic evidence of a negative association between PD and most cancers, a notable exception to this is that melanoma, a malignant tumor of melanin-producing cells in skin, occurs with higher-than-expected frequency among subjects with PD and that melanoma patients are more likely to have PD. A clear biological explanation for this epidemiological observation is lacking. Here, we present a comprehensive review of published literature exploring the association between PD and melanoma. On the basis of published findings, we conclude that (i) changes in pigmentation including melanin synthesis and/or melanin synthesis enzymes, such as tyrosinase and tyrosine hydroxylase, play important roles in altered vulnerability for both PD and melanoma; (ii) changes of PD-related genes such as Parkin, LRRK2 and α-synuclein may increase the risk of melanoma; (iii) changes in some low-penetrance genes such as cytochrome p450 debrisoquine hydroxylase locus, glutathione S-transferase M1 and vitamin D receptor could increase the risk for both PD and melanoma and (iv) impaired autophagy in both PD and melanoma could also explain the association between PD and melanoma. Future studies are required to address whether altered pigmentation, PD- or melanoma-related gene changes and/or changes in autophagy function induce oncogenesis or apoptosis. From a clinical point of view, early diagnosis of melanoma in PD patients is critical and can be enhanced by periodic dermatological surveillance, including skin biopsies. Copyright © 2011 UICC.
Chen S.,Shanghai JiaoTong University |
Chen S.,Baylor College of Medicine |
Zhang X.-J.,Shanghai JiaoTong University |
Xie W.-J.,Diana Helis Henry Medical Research Foundation |
And 4 more authors.
CNS Neuroscience and Therapeutics | Year: 2015
Aims: To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects. Methods: We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting. Results: Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI-641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449. Conclusions: These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD. © 2015 John Wiley & Sons Ltd.
Martin I.,Johns Hopkins University |
Kim J.W.,Johns Hopkins University |
Dawson V.L.,Johns Hopkins University |
Dawson V.L.,Adrienne Helis Malvin Medical Research Foundation |
And 3 more authors.
Journal of Neurochemistry | Year: 2014
Mutations in the catalytic Roc-COR and kinase domains of leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD). LRRK2 mutations cause PD with age-related penetrance and clinical features identical to late-onset sporadic PD. Biochemical studies support an increase in LRRK2 kinase activity and a decrease in GTPase activity for kinase domain and Roc-COR mutations, respectively. Strong evidence exists that LRRK2 toxicity is kinase dependent leading to extensive efforts to identify selective and brain-permeable LRRK2 kinase inhibitors for clinical development. Cell and animal models of PD indicate that LRRK2 mutations affect vesicular trafficking, autophagy, protein synthesis, and cytoskeletal function. Although some of these biological functions are affected consistently by most diseaselinked mutations, others are not and it remains currently unclear how mutations that produce variable effects on LRRK2 biochemistry and function all commonly result in the degeneration and death of dopamine neurons. LRRK2 is typically present in Lewy bodies and its toxicity in mammalian models appears to be dependent on the presence of a-synuclein, which is elevated in human iPS-derived dopamine neurons from patients harboring LRRK2 mutations. Here, we summarize biochemical and functional studies of LRRK2 and its mutations and focus on aberrant vesicular trafficking and protein synthesis as two leading mechanisms underlying LRRK2-linked disease. © 2014 International Society for Neurochemistry.
Welte T.,Diana Helis Henry Medical Research Foundation |
Welte T.,Baylor College of Medicine |
Zhang X.H.-F.,Baylor College of Medicine
Mediators of Inflammation | Year: 2015
Metastatic disease accounts for more than 90% of deaths from breast cancer. Yet the factors that trigger metastasis, often years after primary tumor removal, are not understood well. Recently the proinflammatory cytokine interleukin- (IL-) 17 family has been associated with poor prognosis in breast cancer. Here we review current literature on the pathogenic mechanisms driven by IL-17 during breast cancer progression and connect these findings to metastasis. These include (1) direct effects of IL-17 on tumor cells promoting tumor cell survival and invasiveness, (2) regulation of tumor angiogenesis, and (3) interaction with myeloid derived suppressor cells (MDSCs) to inhibit antitumor immune response and collaborate at the distant metastatic site. Furthermore, IL-17 might also be a culprit in bone destruction caused by late stage bone metastasis. Interestingly, in addition to these potential prometastasis functions, there is also evidence for an opposite, antitumor role of IL-17 during cancer therapies. We hypothesize that these contradictory roles may be due to chronic, imbalanced versus acute transient nature of the immune reactions, as well as differences in the cells that interact with IL-17+ cells under different circumstances. © 2015 Thomas Welte and Xiang H.-F. Zhang.