Type 2 diabetes mellitus (T2DM) is a risk factors for developing Parkinson's disease (PD). Insulin desensitization is observed in the brains of PD patients, which may be an underlying mechanism that promotes neurodegeneration. Incretin hormones are growth factors that can re-sensitize insulin signalling. We have previously shown that analogues of the incretins GLP-1 or GIP have neuroprotective effects in the MPTP mouse model of PD. Novel dual GLP-1/GIP receptor agonists have been developed as treatments for T2DM. We have tested 3 novel dual receptor agonists DA-JC1, DA-JC4 and DA-CH5 in comparison with the GLP-1 analogue liraglutide (all drugs at 25 nmol/kg ip once-daily for 6 days) in the MPTP mouse model of PD (4 × 25 mg/kg ip). In the Rotarod and grip strength assessment, DA-CH5 performed best in reversing the MPTP-induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA-CH5 was the best drug to reverse this. Pro-inflammatory cytokines were best reduced by DA-CH5, while expression levels of the neuroprotective growth factor Glial-Derived Neurotrophic Factor (GDNF) was most increased by DA-JC4. Synapses were protected best by DA-JC4 and DA-CH5. Both DA-JC1 and liraglutide showed inferior effects. These results show that a combination of GLP-1 and GIP receptor activation is more efficient compared to single GLP-1 receptor activation. We conclude that dual agonists are a promising novel treatment for PD. The GLP-1 mimetic exendin-4 has previously shown disease modifying effects in two clinical trials in Parkinson patients.

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease, European Journal of Pharmacology, http://dx.doi.org/10.1016Pharmacology, http://dx.doi.org/10. /j.ejphar.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Alzheimer’s disease (AD) is a widespread neurodegenerative disease caused by complicated disease-causing factors. Unsatisfactorily, curative effects of approved anti-AD drugs were not good enough due to their actions on single-target, which led to desperate requirements for more effective drug therapies involved in multiple pathomechanisms of AD. The anti-AD effect with multiple action targets of Kai-Xin-San (KXS), a classic prescription initially recorded in Bei Ji Qian Jin Yao Fang and applied in the treatment of dementia for thousands of years, was deciphered with modern biological methods in our study. Aβ25-35 and D-gal-induced AD rats and Aβ25-35-induced PC12 cells were applied to establish AD models. KXS could significantly improve cognition impairment by decreasing neurotransmitter loss and enhancing the expression of PI3K/Akt. For the first time, KXS was confirmed to improve the expression of PI3K/Akt by neurotransmitter 5-HT. Thereinto, PI3K/Akt could further inhibit Tau hyperphosphorylation as well as the apoptosis induced by oxidative stress and neuroinflammation. Moreover, all above-mentioned effects were verified and blocked by PI3K inhibitor, LY294002, in Aβ25-35-induced PC12 cells, suggesting the precise regulative role of KXS in the PI3K/Akt pathway. The utilization and mechanism elaboration of KXS have been proposed and dissected in the combination of animal, molecular, and protein strategies. Our results demonstrated that KXS could ameliorate AD by regulating neurotransmitter and PI3K/Akt signal pathway as an effective multitarget treatment so that the potential value of this classic prescription could be explored from a novel perspective.

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Background : Given that the validity of applying complex posttraumatic stress disorder (CPTSD) in nonclinical children remains unclear. Objectives : The current study aimed to explore the factor structure, discriminant validity, and risk factors of ICD-11 posttraumatic stress disorder (PTSD) and CPTSD using the International Trauma Questionnaire. Methods : A total of 3478 trauma-exposed Chinese children aged 9–12 years were included in this study. All participants were assessed for PTSD and CPTSD using the International Trauma Questionnaire (ITQ). Confirmatory factor analysis (CFA) was conducted to explore the factor structure of CPTSD in a sample of Chinese children. Latent class analysis (LCA) was employed to evaluate the discriminant validity of CPTSD symptoms. Multinomial logistic regression analyses determined associations between the different classes and traumatic events. Results : The CFA results showed that the first-order six-factor model was identified as the best-fitting model in Chinese children aged 9–12 years. Four different classes, CPTSD symptoms, PTSD symptoms, disturbances in self-organization (DSO) symptoms, and a low symptom class were found by LCA. Both prolonged interpersonal trauma and other types of trauma were risk factors for the CPTSD class and the PTSD class. Conclusions : The results of this study partially support the factorial validity and strongly support the discriminant validity of the ICD-11 proposals for PTSD and CPTSD in Chinese children, supporting the conceptualization of PTSD and CPTSD as sibling diagnoses based on the ICD-11. However, findings suggest the need for careful consideration of identified trauma types in the ICD-11 proposals.