Regulation of GABAergic neurotransmission by purinergic receptors in brain physiology and disease.

Purinergic receptors regulate the processing of neural information in the hippocampus and cerebral cortex, structures related to cognitive functions. These receptors are activated when astrocytic and neuronal populations release adenosine triphosphate (ATP) in an autocrine and paracrine manner, following sustained patterns of neuronal activity. The modulation by these receptors of GABAergic transmission has only recently been studied. Through their ramifications, astrocytes and GABAergic interneurons reach large groups of excitatory pyramidal neurons. Their inhibitory effect establishes different synchronization patterns that determine gamma frequency rhythms, which characterize neural activities related to cognitive processes. During early life, GABAergic-mediated synchronization of excitatory signals directs the experience-driven maturation of cognitive development, and dysfunctions concerning this process have been associated with neurological and neuropsychiatric diseases. Purinergic receptors timely modulate GABAergic control over ongoing neural activity and deeply affect neural processing in the hippocampal and neocortical circuitry. Stimulation of A2 receptors increases GABA release from presynaptic terminals, leading to a considerable reduction in neuronal firing of pyramidal neurons. A1 receptors inhibit GABAergic activity but only act in the early postnatal period when GABA produces excitatory signals. P2X and P2Y receptors expressed in pyramidal neurons reduce the inhibitory tone by blocking GABAA receptors. Finally, P2Y receptor activation elicits depolarization of GABAergic neurons and increases GABA release, thus favoring the emergence of gamma oscillations. The present review provides an overall picture of purinergic influence on GABAergic transmission and its consequences on neural processing, extending the discussion to receptor subtypes and their involvement in the onset of brain disorders, including epilepsy and Alzheimer's disease.

Distinct Effects of the Hippocampal Transplantation of Neural and Mesenchymal Stem Cells in a Transgenic Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a severe disabling condition with no cure currently available, which accounts for 60-70% of all dementia cases worldwide. Therefore, the investigation of possible therapeutic strategies for AD is necessary. To this end, animal models corresponding to the main aspects of AD in humans have been widely used. Similar to AD patients, the double transgenic APPswe/PS1dE9 (APP/PS1) mice show cognitive deficits, hyperlocomotion, amyloid-ß (Αß) plaques in the cortex and hippocampus, and exacerbated inflammatory responses. Recent studies have shown that these neuropathological features could be reversed by stem cell transplantation. However, the effects induced by neural (NSC) and mesenchymal (MSC) stem cells has never been compared in an AD animal model. Therefore, the present study aimed to investigate whether transplantation of NSC or MSC into the hippocampus of APP/PS1 mice reverses AD-induced pathological alterations, evaluated by the locomotor activity (open field test), short- and long-term memory (object recognition) tests, Αß plaques (6-E10), microglia distribution (Iba-1), M1 (iNOS) and M2 (ARG-1) microglial phenotype frequencies. NSC and MSC engraftment reduced the number of Αß plaques and produced an increase in M2 microglia polarization in the hippocampus of APP/PS1 mice, suggesting an anti-inflammatory effect of stem cell transplantation. NSC also reversed the hyperlocomotor activity and increased the number of microglia in the hippocampus of APP/PS1 mice. No impairment of short or long-term memory was observed in APP/PS1 mice. Overall, this study highlights the potential beneficial effects of transplanting NSC or MSC for AD treatment.

Protective effect of CD73 inhibitor α, ß-methylene ADP against amyloid-ß-induced cognitive impairment by inhibiting adenosine production in hippocampus

BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease. Recent studies have reported the close association between cognitive function in AD and purinergic receptors in the central nervous system. In the current study, we investigated the effect of CD73 inhibitor α, ß-methylene ADP (APCP) on cognitive impairment of AD in mice, and to explore the potential underlying mechanisms. RESULTS: We found that acute administration of Aß1­42 (i.c.v.) resulted in a significant increase in adenosine release by using microdialysis study. Chronic administration of APCP (10, 30 mg/kg) for 20 d obviously mitigated the spatial working memory impairment of Aß1­42-treated mice in both Morris water maze (MWM) test and Y-maze test. In addition, the extracellular adenosine production in the hippocampus was inhibited by APCP in Aß-treated mice. Further analyses indicated expression of acetyltransferase (ChAT) in hippocampus of mice of was significantly reduced, while acetylcholinesterase (AChE) expression increased, which compared to model group. We observed that APCP did not significantly alter the NLRP3 inflammasome activity in hippocampus, indicating that anti-central inflammation seems not to be involved in APCP effect. CONCLUSIONS: In conclusion, we report for the first time that inhibition of CD73 by APCP was able to protect against memory loss induced by Aß1­42 in mice, which may be due to the decrease of CD73-driven adenosine production in hippocampus. Enhancement of central cholinergic function of the central nervous system may also be involved in the effects of APCP.

Purinergic Receptors in Basal Ganglia Diseases: Shared Molecular Mechanisms between Huntington's and Parkinson's Disease.

Huntington's (HD) and Parkinson's diseases (PD) are neurodegenerative disorders caused by the death of GABAergic and dopaminergic neurons in the basal ganglia leading to hyperkinetic and hypokinetic symptoms, respectively. We review here the participation of purinergic receptors through intracellular Ca2+ signaling in these neurodegenerative diseases. The adenosine A2A receptor stimulates striatopallidal GABAergic neurons, resulting in inhibitory actions on GABAergic neurons of the globus pallidus. A2A and dopamine D2 receptors form functional heteromeric complexes inducing allosteric inhibition, and A2A receptor activation results in motor inhibition. Furthermore, the A2A receptor physically and functionally interacts with glutamate receptors, mainly with the mGlu5 receptor subtype. This interaction facilitates glutamate release, resulting in NMDA glutamate receptor activation and an increase of Ca2+ influx. P2X7 receptor activation also promotes glutamate release and neuronal damage. Thus, modulation of purinergic receptor activity, such as A2A and P2X7 receptors, and subsequent aberrant Ca2+ signaling, might present interesting therapeutic potential for HD and PD.

Phosphorylation of eIF2α mitigates endoplasmic reticulum stress and hepatocyte necroptosis in acute liver injury.

INTRODUCTION AND OBJECTIVES: Necroptosis and endoplasmic reticulum (ER) stress has been implicated in acute and chronic liver injury. Activated eukaryotic initiation factor 2 alpha (eIF2α) attenuates protein synthesis and relieves the load of protein folding in the ER. In this study, we aimed to analyze the impact of eIF2α phosphorylation on hepatocyte necroptosis in acute liver injury. MATERIALS AND METHODS: Male BALB/c mice were injected with tunicamycin or d-galactosamine, and LO2 cells were incubated with tunicamycin to induce acute liver injury. 4-Phenylbutyric acid (PBA) and salubrinal were used to inhibit ER stress and eIF2α dephosphorylation, respectively. We analyzed the eIF2α phosphorylation, ER stress, and hepatocyte necroptosis in mice and cells model. RESULTS: Tunicamycin or d-galactosamine significantly induced ER stress and necroptosis, as well as eIF2α phosphorylation, in mice and LO2 cells (p<0.05). ER stress aggravated tunicamycin-induced hepatocyte necroptosis in mice and LO2 cells (p<0.05). Elevated eIF2α phosphorylation significantly mitigated hepatocyte ER stress (p<0.05) and hepatocyte necroptosis in mice (34.37±3.39% vs 22.53±2.18%; p<0.05) and LO2 cells (1±0.11 vs 0.33±0.05; p<0.05). Interestingly, tumor necrosis factor receptor (TNFR) 1 protein levels were not completely synchronized with necroptosis. TNFR1 expression was reduced in d-galactosamine-treated mice (p<0.05) and cells incubated with tunicamycin for 12 and 24h (p<0.05). ER stress partially restored TNFR1 expression and increased necroptosis in tunicamycin-incubated cells (p<0.05). CONCLUSIONS: These results imply that ER stress can mediate hepatocyte necroptosis independent of TNFR1 signaling and elevated eIF2α phosphorylation can mitigate ER stress during acute liver injury.

Short-term efficacy and safety of low-intensity extracorporeal shock wave therapy in erectile dysfunction: a systematic review and meta-analysis

ABSTRACT Aim: The role of low-intensity extracorporeal shock wave therapy (LI-ESWT) in erectile dysfunction (ED) is not clearly determined. The purpose of this study is to investigate the short-term efficacy and safety of LI-ESWT for ED patients. Materials and Methods: Relevant studies were searched in Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and VIP databases. Effective rate in terms of International Index of Erectile Function-Erectile Function Domain (IIEF-EF) and Erectile Hardness Score (EHS) at about 1XSmonth after LI-ESWT was extracted from eligible studies for meta-analysis to calculate risk ratio (RR) of effective treatment in ED patients treated by LI-ESWT compared to those receiving sham-treatment. Results: Overall fifteen studies were included in the review, of which four randomized controlled trials (RCTs) were for meta-analysis. Effective treatment was 8.31 [95°/o confidence interval (CI): 3.88-17.78] times more effective in the LI-ESWT group (n=176) than in the sham-treatment group (n= 101) at about 1 month after the intervention in terms of EHS, while it was 2.50 (95% CI: 0.74-8.45) times more in the treatment group (n= 121) than in the control group (n=89) in terms of IIEF-EF. Nine-week protocol with energy density of 0.09mJ/mm2 and 1500 pluses seemed to have better therapeutic effect than five-week protocol. No significant adverse event was reported. Conclusion: LI-ESWT, as a noninvasive treatment, has potential short-term therapeutic effect on patients with organic ED irrespective of sensitivity to PDE5is. Owing to the limited number and quality of the studies, more large-scale, well-designed and longterm follow-up time studies are needed to confirm our analysis.

Short-term efficacy and safety of low-intensity extracorporeal shock wave therapy in erectile dysfunction: a systematic review and meta-analysis.

AIM: The role of low-intensity extracorporeal shock wave therapy (LI-ESWT) in erectile dysfunction (ED) is not clearly determined. The purpose of this study is to investigate the short-term efficacy and safety of LI-ESWT for ED patients. MATERIALS AND METHODS: Relevant studies were searched in Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), WANFANG and VIP databases. Effective rate in terms of International Index of Erectile Function-Erectile Function Domain (IIEF-EF) and Erectile Hardness Score (EHS) at about 1month after LI-ESWT was extracted from eligible studies for meta-analysis to calculate risk ratio (RR) of effective treatment in ED patients treated by LI-ESWT compared to those receiving sham-treatment. RESULTS: Overall fifteen studies were included in the review, of which four randomized controlled trials (RCTs) were for meta-analysis. Effective treatment was 8.31 [95% confidence interval (CI): 3.88-17.78] times more effective in the LI-ESWT group (n=176) than in the sham-treatment group (n=101) at about 1 month after the intervention in terms of EHS, while it was 2.50 (95% CI: 0.74-8.45) times more in the treatment group (n=121) than in the control group (n=89) in terms of IIEF-EF. Nine-week protocol with energy density of 0.09mJ/mm2 and 1500 pluses seemed to have better therapeutic effect than five-week protocol. No significant adverse event was reported. CONCLUSION: LI-ESWT, as a noninvasive treatment, has potential short-term therapeutic effect on patients with organic ED irrespective of sensitivity to PDE5is. Owing to the limited number and quality of the studies, more large-scale, well-designed and long-term follow-up time studies are needed to confirm our analysis.

Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children.

OBJECTIVE: The study goal was to determine the diagnostic accuracy of a specific cytokine pattern including interferon-gamma (IFN-γ), interleukin (IL)-10, and IL-6 for hemophagocytic lymphohistiocytosis (HLH) in febrile children. STUDY DESIGN: In this prospective study, 756 patients with fever admitted to a hematology-oncology unit were enrolled. The causes of fever were documented and the serum cytokines, including IFN-γ, tumor necrosis factor-alpha (TNF-α), IL-10, IL-6, IL-4, and IL-2, were determined using cytometric bead array techniques. RESULTS: Of 1474 episodes of fever that were analyzed, 71 episodes of HLH manifested a specific cytokine pattern of highly increased levels of IFN-γ (median level: 1088.5 pg/mL) and IL-10 (623.5 pg/mL) but a moderately increased level of IL-6 (51.1 pg/mL). IL-6 was predominantly increased to varied extents in patients in the sepsis group (244.6 pg/mL) and the nonsepsis infection group (34.7 pg/mL). The diagnostic accuracy of IFN-γ and IL-10 for HLH was 99.5% and 92.8%, respectively. By applying the cutoff point of 100 pg/mL, IFN-γ had a sensitivity of 94.4% and a specificity of 97.2% for HLH. When using the criteria of IFN-γ >75 pg/mL and IL-10 >60 pg/mL, the specificity reached 98.9% and the sensitivity was 93.0%. CONCLUSIONS: The specific cytokine pattern of markedly elevated levels of IFN-γ and IL-10 with only modestly elevated IL-6 levels has high diagnostic accuracy for HLH and may be a useful approach to differentiate HLH from infection.