CCL2 Potentiates Inflammation Pain and Related Anxiety-Like Behavior Through NMDA Signaling in Anterior Cingulate Cortex.

Previous studies have shown that the C-C motif chemokine ligand 2 (CCL2) is widely expressed in the nervous system and involved in regulating the development of chronic pain and related anxiety-like behaviors, but its precise mechanism is still unclear. This paper provides an in-depth examination of the involvement of CCL2-CCR2 signaling in the anterior cingulate cortex (ACC) in intraplantar injection of complete Freund's adjuvant (CFA) leading to inflammatory pain and its concomitant anxiety-like behaviors by modulation of glutamatergic N-methyl-D-aspartate receptor (NMDAR). Our findings suggest that local bilateral injection of CCR2 antagonist in the ACC inhibits CFA-induced inflammatory pain and anxiety-like behavior. Meanwhile, the expression of CCR2 and CCL2 was significantly increased in ACC after 14 days of intraplantar injection of CFA, and CCR2 was mainly expressed in excitatory neurons. Whole-cell patch-clamp recordings showed that the CCR2 inhibitor RS504393 reduced the frequency of miniature excitatory postsynaptic currents (mEPSC) in ACC, and CCL2 was involved in the regulation of NMDAR-induced current in ACC neurons in the pathological state. In addition, local injection of the NR2B inhibitor of NMDAR subunits, Ro 25-6981, attenuated the effects of CCL2-induced hyperalgesia and anxiety-like behavior in the ACC. In summary, CCL2 acts on CCR2 in ACC excitatory neurons and participates in the regulation of CFA-induced pain and related anxiety-like behaviors through upregulation of NR2B. CCR2 in the ACC neuron may be a potential target for the treatment of chronic inflammatory pain and pain-related anxiety.

Peripheral BDNF Regulates Somatosensory-Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain.

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.

Intracoronary pressure gradient measurement in acute myocardial infarction patients with the no-reflow phenomenon during primary percutaneous coronary intervention.

BACKGROUND: Various experimental and clinical studies have reported on coronary microcirculatory dysfunction ("no-reflow" phenomenon). Nevertheless, pathogenesis and effective treatment are yet to be fully elucidated. This study aimed to measure the intracoronary pressure gradient in the no-reflow artery during emergent percutaneous coronary intervention and explore the potential mechanism of no-reflow. METHODS: From September 1st, 2018 to June 30th, 2019, intracoronary pressure in acute myocardial infarction patient was continuously measured by aspiration catheter from distal to proximal segment in the Department of Coronary Care Unit, Tianjin Chest Hospital, respectively in no-reflow arteries (no-reflow group) and arteries with thrombolysis in myocardial infarction-3 flow (control group). At least 12 cardiac cycles were consecutively recorded when the catheter was pulled back. The forward systolic pressure gradient was calculated as proximal systolic pressure minus distal systolic pressure. Comparison between groups was made using the Student t test, Mann-Whitney U-test or Chi-square test, as appropriate. RESULTS: Intracoronary pressure in 33 no-reflow group and 26 in control group were measured. The intracoronary forward systolic pressure gradient was -1.3 (-4.8, 0.7) and 3.8 (0.8, 8.8) mmHg in no-reflow group and control group (Z = -3.989, P < 0.001), respectively, while the forward diastolic pressure gradient was -1.0 (-3.2, 0) and 4.6 (0, 16.5) mmHg in respective groups (Z = -3.851, P < 0.001). Moreover, the intracoronary forward pressure gradient showed significant difference between that before and after nicorandil medication (Z = -3.668, P < 0.001 in systolic pressure gradient and Z = -3.530, P < 0.001 in diastolic pressure gradient). CONCLUSIONS: No reflow during emergent coronary revascularization is significantly associated with local hemodynamic abnormalities in the coronary arteries. Intracoronary nicorandil administration at the distal segment of a coronary artery with an aspiration catheter could improve the microcirculatory dysfunction and resume normal coronary pressure gradient. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov (No. NCT03600259).

Anti-hyperglycemic effect of fangchinoline isolated from Stephania tetrandra Radix in streptozotocin-diabetic mice.

Kampo medicine, Stephania tetrandra Radix (Stephania) in Boi-ogi-to increases the blood insulin level and falls the blood glucose level in streptozotocin (STZ)-diabetic ddY mice. These actions of Stephania are potentiated by Astragalus membranaceus Bunge Radix (Astragali) in Boi-ogi-to (Liu et al., J. Traditional Med., 17, 253-260, 2000). In the present study, actions of bis-benzylisoquinoline alkaloids isolated from Stephania were investigated in the hyperglycemia of STZ-diabetic mice. A main bis-benzylisoquinoline alkaloid, fangchinoline (0.3-3 mg/kg) significantly fell the blood glucose level of the diabetic mice in a dose-dependent manner. The effect of fangchinoline was 3.9-fold greater than that of water extract of Stephania. However, another main compound, tetrandrine (1-100 mg/kg) did not have any effect. The water extract of Astragali did not affect singly but potentiated the anti-hyperglycemic action of fangchinoline (0.3 mg/kg). Out of used compounds (1 mg/kg) isolated from Stephania, fangchinoline, fangchinoline 2'-N-alpha-oxide and 2'-N-norfangchinoline, which are substituted with 7-hydroxy side chain for 7-O-methyl side chain, decreased to near 50% of high blood glucose level. In addition, tetrandrine 2'-N-beta-oxide, tetrandrine 2'-N-alpha-oxide, tetrandrine 2-N-beta-oxide, fangchinoline 2'-N-alpha-oxide, which are added to 2- or 2'-N-oxide side chain, also decreased to near 50% of the high blood glucose level. In conclusion, fangchinoline but not tetrandrine from Stephania shows the anti-hyperglycemic action in the STZ-diabetic mice. The demethylation of 7-O-position and/or addition of 2- or 2'-N-oxide side chain in bis-benzylisoquinoline compounds in Stephania have a role for the induction of the anti-hyperglycemic actions.