Dynamic Changes in the Renin-Angiotensin-Aldosterone System and the Beneficial Effects of Renin-Angiotensin-Aldosterone Inhibitors on Spatial Learning and Memory in a Rat Model of Chronic Cerebral Ischemia

Renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and brain function. Therefore, we studied the dynamic changes in the RAAS in the blood, cerebral cortex, and hippocampus and the effects of RAAS inhibitors on spatial learning and memory and hippocampal apoptosis in a rat model of chronic cerebral ischemia (CCI) established by bilateral ligation of the common carotid arteries of rats. The levels of renin, angiotensin II (Ang II), and aldosterone (ALD) in the plasma, and the homogenates of the left side of cerebral cortex and whole hippocampus of rats were detected on day 1, 3, 7, 14, 21, and 30 by radioimmunoassay. Spatial learning and memory and hippocampal apoptosis were evaluated on day 30 by Morris water maze test (navigation and space exploration tests) and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, respectively, after rats were orally administered with distilled water (DW), renin inhibitor aliskiren (30 mg/kg), Ang converting enzyme inhibitor enalapril (4 mg/kg), or Ang II receptor antagonist candesartan (2 mg/kg) daily for 30 days. The results showed that the levels of renin and Ang II were significantly higher but ALD fluctuated in the blood, cerebral cortex, and hippocampus in CCI rats compared to normal rats. However, aliskiren and enalapril could significantly decrease (p < 0.05) the levels of renin, Ang II and ALD in the blood, cerebral cortex, and hippocampus compared to DW treatment; while candesartan had similar effect on renin and ALD but no effect on Ang II in CCI rats. Furthermore, spatial learning and memory were significantly decreased but apoptosis in the hippocampus was obviously increased in CCI rats compared to normal rats (p < 0.05). However, aliskiren, enalapril, and candesartan were equally effective to improve spatial learning and memory and decrease apoptosis in the hippocampus. Therefore, RAAS plays an important role in the development of cerebral ischemia and RAAS inhibitors aliskiren, enalapril, and candesartan improve spatial learning and memory and protect brain injury by inhibiting hippocampal apoptosis in CCI rats

Breakthrough Cancer Pain Is Associated with Spinal Gap Junction Activation via Regulation of Connexin 43 in a Mouse Model

Breakthrough cancer pain (BTcP) is a high-intensity, short-duration, unpredictable and uncontrollable pain. Recent studies have shown that activation of gap junction (GJ) in spinal cord plays an important role in the pathogenesis of BTcP. We examined the expressions of Glial fibrillary acidic protein (GFAP), connexin (Cx) 43 protein and phosphorylation of Cx43 (p-Cx43) in the spinal cord of mice. In addition, we investigated the effects of Gap26, a selective GJ blocker, on the expressions of GFAP, Cx43 and p-Cx43 in BTcP mice. We found that the expressions of GFAP and Cx43 proteins were significantly upregulated while p-Cx43 was down-regulated in the spinal cord in a mouse model of BTcP. The overexpression of Cx43 protein in the spinal cord increased GJ formation and enhanced BTcP. The variation of the ratio of p-Cx43/T-Cx43 (total Cx43) affected the function of GJ to induce BTcP. Furthermore, BTcP was alleviated by Gap26 via reducing pain hypersensitivity. The inhibition of Cx43 and p-Cx43 by Gap26 attenuated BTcP but the p/T ratio of Cx43 remained unchanged in BTcP mice. We reveal that the expression and phosphorylation of Cx43 affected BTcP and GJ activation facilitated BTcP via a Cx43-mediated signaling in the spinal cord. The finding may provide a scientific rationale for discovery and development of novel therapeutic targets for the treatment of BTcP clinically

Inhibition of Connexin 43 and Phosphorylated NR2B in Spinal Astrocytes Attenuates Bone Cancer Pain in Mice

Bone cancer pain (BCP) is common in patients with advanced cancers when the tumors are metastasized to bone. The limited understanding of the complex pathogenesis of BCP leads to the poor effectiveness of clinical treatment. Previous studies have shown that astrocyte-specific connexin (Cx) 43, a forming protein of gap junction (GJ) and hemichannel, and N-methyl-D-aspartate receptors (NMDARs), especially the phosphorylated NMDAR 2B subunit (NR2B) phosphorylated NR2B (p-NR2B) subunit are involved in BCP. However, the relationship between Cx43 and p-NR2B in BCP remains unclear. In the present study, we investigated the expressions of Cx43, glial fibrillary acidic protein (GFAP, a marker of astrocytes), and p-NR2B in the spinal dorsal horn (SDH) in a mouse model of BCP established by intra-femural inoculation of Lewis lung carcinoma (LLC) cells via intrathecal (ith) injection of the GJ/hemichannel blocker carbenoxolone (CARB) and the NMDAR antagonist MK801, respectively. We found that the characters of BCP were mimicked by intra-femural inoculation of LLC cells in mice, and the expressions of Cx43, GFAP and p-NR2B in BCP mice were remarkably increased in a time-dependent manner from day 7 to day 21 after cell inoculation with a gradual aggravate in spontaneous pain and mechanical allodynia. Furthermore, Cx43 was predominantly expressed in the spinal astrocytes. Both CARB and MK801 inhibited the expressions of Cx43, GFAP and p-NR2B with attenuated pain hypersensitivity in BCP mice. In addition, Cx43 was co-localized with p-NR2B in the SDH, which further evidenced the presence of functional NR2B in the spinal astrocytes in BCP mice. Our findings demonstrate that inhibition of Cx43 and p-NR2B in spinal astrocytes could attenuate BCP in mice and Cx43 and p-NR2B in the astrocytes of the SDH may play an important role via their combination action in the development and maintenance of BCP in mice. These results may provide a potential therapeutic target in the prevention and/or treatment of BCP

Efficacy and Safety of Teneligliptin in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Teneligliptin is a 3rd-generation dipeptidyl peptidase-4 (DPP-4) inhibitor. There is a limited evidence regarding the effect of teneligliptin. Therefore, this study is to assess the efficacy and safety of teneligliptin in type 2 diabetes mellitus (T2DM) patients with inadequately glycemic controlled.Methods: A search of PubMed, Medline, Embase, and The Cochrane Library during 2000.01–2018.03 was performed for randomized controlled trials of teneligliptin compared to placebo in patients with T2DM with monotherapy or add-on treatment.Results: Ten trials with 2119 patients were analyzed. Teneligliptin produced absolute reductions in glycated hemoglobin A1c (HbA1c) levels (weighted mean difference (WMD) 0.82%, 95% confidence interval (CI) [−0.91 to −0.72], p < 0.00001) compared with placebo. However, after 36–42 weeks of follow-up (open-label), HbA1c level rise higher than duration (double-blind) in teneligliptin group. Teneligliptin led to greater decrease of fasting plasma glucose (FPG) level (vs. placebo, WMD −18.32%, 95% CI [−21.05 to −15.60], p < 0.00001). Teneligliptin also significantly decreased the 2 h post-prandial plasma glucose (2 h PPG) (WMD −46.94%, 95% CI [−51.58 to −42.30], p < 0.00001) and area under the glucose plasma concentration-time curve from 0 to 2 h (AUC0−2h) for PPG (WMD −71.50%, 95% CI [−78.09 to −64.91], p < 0.00001) compared with placebo. Patients treated with teneligliptin achieved increased homeostasis model assessment of β cell function (HOMA-β) with 9.31 (WMD, 95% CI [7.78–10.85], p < 0.00001). However, there was no significant difference between teneligliptin and placebo in overall adverse effects (0.96 risk ratio (RR), 95% CI [0.87, 1.06], p = 0.06). The risks of hypoglycemia were not significantly different between teneligliptin and placebo (1.16 RR, 95% CI [0.59, 2.26], p = 0.66).Conclusions: Teneligliptin improved blood glucose levels and β-cells function with low risk of hypoglycemia in patients with T2DM. Common adverse effects of teneligliptin including hypoglycemia were identified and reviewed. Risks of cardiovascular events are less certain, and more data for long-term effects are needed