Further clarification of cognitive processes of prospective memory in schizophrenia by comparing eye-tracking and ecologically-valid measurements.

The aim of this study is to compare ecologically-valid measure (the Cambridge Prospective Memory Test, CAMPROMPT) and laboratory measure (eye-tracking paradigm) in assessing prospective memory (PM) in individuals with schizophrenia spectrum disorders (SSDs). In addition, eye-tracking indices are used to examine the relationship between PM and other cognitive domains in SSDs patients. Initially, the study sample was formed by 32 SSDs patients and 32 healthy control subjects (HCs) who were matched in sociodemographic profile and the performance on CAMPROMPT. An eye-tracking paradigm was employed to examine the differences in PM accuracy and key cognitive processes (e.g., cue monitoring) between the two groups. Additional 31 patients were then recruited to investigate the relationship between PM cue monitoring, other cognitive functions, and the severity of clinical symptoms within the SSDs group. The monitoring of PM cue was reflected in total fixation time and total fixation counts for distractor words. Cognitive functions were assessed using the Chinese version of the MATRICS Consensus Cognitive Battery (MCCB). The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathology. SSDs patients exhibited fewer total fixation counts for distractor words and lower PM accuracy compared to HCs, even though they were priori matched on CAMPROMPT. Correlation analysis within the SSDs group (63 cases) indicated a negative correlation between PM accuracy and PANSS total score, and a positive correlation with working memory and attention/vigilance. Regression analysis within the SSDs group revealed that higher visual learning and lower PANSS total scores independently predicted more total fixation counts on distractor words. Impairment in cue monitoring is a critical factor in the PM deficits in SSDs. The eye-tracking laboratory paradigm has advantages over the ecologically-valid measurement in identifying the failure of cue detection, making it a more sensitive tool for PM deficits in patients with SSDs.

The deficient cue monitoring and the facilitating effect of prosocial intention on prospective memory in patients with schizophrenia spectrum disorders.

The study aimed to investigate the cognitive processing of prospective memory (PM) in patients with schizophrenia spectrum disorders (SSDs) by using an eye-tracking paradigm. In addition, the facilitating effects of prosocial intention (the desire to help others) on PM in SSDs were also examined. In phase 1, 26 patients (group1) and 25 healthy controls (HCs) were compared in an eye-tracking PM paradigm in terms of the PM accuracy and eye-tracking indices. In phase 2, 21 more patients (group2) were recruited, and a prosocial intention was introduced in the eye-tracking PM paradigm. Their PM accuracy and eye-tracking indices were compared with those in group1. The PM cue monitoring was indicated by the total fixation counts and fixation time on distractor words. In phase 1, group1 showed lower PM accuracy, fewer fixation counts and less fixation time on distractor words than HCs. In phase 2, group2 (with prosocial intention) performed significantly better than group1 (with typical instruction) on both PM accuracy and fixation time on distractor words. In both groups of SSDs, the PM accuracy was significantly correlated with both the fixation counts and the fixation time of distractor words. After controlling for the cue monitoring indices, the difference in PM accuracy remained significant between group1 and HCs but disappeared between group1 and group2. The cue monitoring deficit contributes to the PM impairment in SSDs. The facilitating effect of prosocial intention disappears after the control of cue monitoring, also indicating its critical role in PM.

[Antibiotic use in very low birth weight/extremely low birth weight infants in 15 hospitals in Jiangsu Province of China: a multicenter survey]. / 江苏省15家医院极低/è¶ ä½Žå‡ºç”Ÿä½“é‡å„¿æŠ—ç”Ÿç´ ä½¿ç”¨çŽ°çŠ¶è°ƒæŸ¥.

OBJECTIVES: To investigate the current status of antibiotic use in very low birth weight/extremely low birth weight infants in Jiangsu Province of China, and to provide a clinical basis for the quality and improvement of antibiotic management in the neonatal intensive care unit (NICU). METHODS: A retrospective analysis was performed on the data on general conditions and antibiotic use in the very low birth weight/extremely low birth weight infants who were admitted to 15 hospitals of Jiangsu Province from January 1, 2019 to December 31, 2020. A questionnaire containing 10 measures to reduce antibiotic use was designed to investigate the implementation of these intervention measures. RESULTS: A total of 1 920 very low birth weight/extremely low birth weight infants were enrolled, among whom 1 846 (96.15%) were treated with antibiotic, and the median antibiotic use rate (AUR) was 50/100 patient-days. The AUR ranged from 24/100 to 100/100 patient-days in the 15 hospitals. After adjustment for the confounding factors including gestational age, birth weight, and neonatal critical score, the Poisson regression analysis showed that there was a significant difference in the adjusted AUR (aAUR) among the hospitals (P<0.01). The investigation results showed that among the 10 measures to reduce antibiotic use, 8 measures were implemented in less than 50% of these hospitals, and the number of intervention measures implemented was negatively correlated with aAUR (rs=-0.564, P=0.029). CONCLUSIONS: There is a high AUR among the very low birth weight/extremely low birth weight infants in the 15 hospitals of Jiangsu Province, with a significant difference among hospitals. The hospitals implementing a relatively few measures to reduce antibiotic use tend to have a high AUR. It is expected to reduce AUR in very low birth weight/extremely low birth weight infants by promoting the quality improvement of antibiotic use management in the NICU.

Chinese herbal formula shen-ling-bai-zhu-san to treat chronic gastritis: Clinical evidence and potential mechanisms.

BACKGROUND: Chronic gastritis (CG) is an inflammatory disease of the gastric mucosa. Shen-ling-bai-zhu san (SLBZS), a traditional Chinese medicine formula, is widely used for treating CG. Nevertheless, its effects are currently unclear. AIM: To determine the clinical evidence and potential mechanisms of SLBZS for the treatment of CG. METHODS: We systematically searched 3 English (PubMed, Embase, Medline) and 4 Chinese databases (Cochrane Library Central Register of Controlled Trials, China National Knowledge Infrastructure database, Wanfang Data Knowledge Service Platform, and the VIP information resource integration service platform) without language or publication bias restriction. Qualified studies were selected according to pre-set inclusion and exclusion criteria. RevMan 5.3 software was used for meta-analysis and literature quality assessment, Stata 14.0 software was used for sensitivity analysis, GRADE profiler 3.6 was used to evaluate the quality of evidence. And then, network pharmacology analysis was applied to primary research the mechanisms of action of SLBZS on CG. RESULTS: Fourteen studies were finally included, covering 1335 participants. Meta-analysis indicated that: (1) SLBZS was superior to conventional therapies [risk ratio (RR): 1.29, 95% confidence interval (CI): 1.21 to 1.37, P < 0.00001]; (2) SLBZS was better than conventional therapies [RR: 0.24, 95% confidence interval (95%CI): 0.11 to 0.55, P = 0.0007] in terms of recurrence rate and reversal of Helicobacter pylori positivity (RR: 1.20, 95%CI: 1.11 to 1.30, P < 0.00001); and (3) The safety of SLBZS for CG remains unclear. According to the GRADE method, the quality of evidence was not high. Besides, SNZJS might treat CG by acting on related targets and pathways such as EGFR tyrosine kinase inhibitor resistance, the PI3K-Akt signaling pathway, and others. CONCLUSION: SLBZS might be useful in treating CG, but long-term effects and specific clinical mechanisms of it maintain unclear. More samples and high-quality clinical experiments should be assessed and verified in the next step.

A multicenter retrospective study on survival rate and complications of very preterm infants. / æžæ—©äº§å„¿å­˜æ´»çŽ‡å’Œå¹¶å‘ç—‡çš„å¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To study the survival rate and the incidence of complications of very preterm infants and the factors influencing the survival rate and the incidence of complications. METHODS: The medical data of the very preterm infants with a gestational age of <32 weeks and who were admitted to the Department of Neonatology in 11 hospitals of Jiangsu Province in China from January 2018 to December 2019 were retrospectively reviewed. Their survival rate and the incidence of serious complications were analyzed. A multivariate logistic regression analysis was used to evaluate the risk factors for death and serious complications in very preterm infants. RESULTS: A total of 2 339 very preterm infants were enrolled, among whom 2 010 (85.93%) survived and 1 507 (64.43%) survived without serious complications. The groups with a gestational age of 22-25+6 weeks, 26-26+6 weeks, 27-27+6 weeks, 28-28+6 weeks, 29-29+6 weeks, 30-30+6 weeks, and 31-31+6 weeks had a survival rate of 32.5%, 60.6%, 68.0%, 82.9%, 90.1%, 92.3%, and 94.8% respectively. The survival rate tended to increase with the gestational age (P<0.05) and the survival rate without serious complications in each gestational age group was 7.5%, 18.1%, 34.5%, 52.2%, 66.7%, 75.7%, and 81.8% respectively, suggesting that the survival rate without serious complications increased with the gestational age (P<0.05). The multivariate logistic regression analysis showed that high gestational age, high birth weight, and prenatal use of glucocorticoids were protective factors against death in very preterm infants (P<0.05), and 1-minute Apgar score ≤3 was a risk factor for death in very preterm infants (P<0.05); high gestational age and high birth weight were protective factors against serious complications in very preterm infants who survived (P<0.05), while 5-minute Apgar score ≤3 and maternal chorioamnionitis were risk factors for serious complications in very preterm infants who survived (P<0.05). CONCLUSIONS: The survival rate is closely associated with gestational age in very preterm infants. A low 1-minute Apgar score (≤3) may increase the risk of death in very preterm infants, while high gestational age, high birth weight, and prenatal use of glucocorticoids are associated with the reduced risk of death. A low 5-minute Apgar score (≤3) and maternal chorioamnionitis may increase the risk of serious complications in these infants, while high gestational age and high birth weight may reduce the risk of serious complications.

TLR4 deficiency abrogated widespread tactile allodynia, but not widespread thermal hyperalgesia and trigeminal neuropathic pain after partial infraorbital nerve transection.

Pain sensitization after partial infraorbital nerve transection (p-IONX) in mice not only presents in orofacial region, but also spreads to distant body parts. The roles of toll-like receptor 4 (TLR4) in orofacial pain and the spreading process are still unclear. Here, we found that mice with deficient TLR4 because of Tr4 gene point mutation (C3H/HeJ) or spontaneous deletion (C57BL/10ScNJ) developed tactile allodynia and thermal hyperalgesia in the vibrissal pad in a parallel way to their respective wild types (C3HeB/FeJ or C57BL/6J) after p-IONX. However, allodynia in the hind paw was absent in mice with TLR4 deficiency. Pharmacological antagonism of TLR4 with LPS-RS, administered either intracisternally or intrathecally, abrogated allodynia in the hind paw without affecting the hypersensitivity in the vibrissal pad and hyperalgesia in the hind paw. Although TNF-α expression was upregulated in both the medulla and lumbar cord, the expression of TLR4 downstream molecule MyD88 increased only in the lumbar cord after p-IONX in wild types. By contrast, hind paw hypersensitivity after partial sciatic nerve ligation was significantly attenuated by TLR4 deletion. The hypersensitivity, which did not spread to the vibrissal pad, was accompanied with upregulation of MyD88 in the lumbar cord rather than in the medulla. These results suggest that TLR4 participates in the spread of allodynia component of orofacial pain to distant body sites, but not trigeminal neuropathic pain or the spread of its hyperalgesia component. This study suggests that TLR4 may serve as a potential target for the management of widespread allodynia associated with orofacial pain.

Pre-stroke Metformin Treatment is Neuroprotective Involving AMPK Reduction.

Long-term metformin treatment reduces the risk of stroke. However, the effective administration pattern and indications of metformin on acute cerebral ischemia are unclear. To investigate the neuroprotective treatment duration and dosage of metformin on focal ischemia mice and the association of neuroprotection with 5'-adenosine monophosphate-activated protein kinase (AMPK) regulations, male C57BL/6 mice were subjected to permanent or transient middle cerebral artery occlusion (MCAO) and metformin of 3, 10 and 30 mg/kg was intraperitoneally injected 1, 3 or 7 days prior to MCAO, or at the onset, or 1, 3 or 6 h after reperfusion, respectively. Infarct volumes, neurological deficit score, cell apoptosis, both total and phosphorylated AMPK expressions were assessed. Results showed that prolonged pretreatment to 7 days of metformin (10 mg/kg) significantly ameliorated brain infarct, neurological scores and cell apoptosis in permanent MCAO mice. Shorter (3 days or 1 day) or without pretreatment of metformin was not effective, suggesting a pretreatment time window. In transient MCAO mice, metformin showed no neuroprotection even with pretreatment. The expressions of total and phosphorylated AMPK were sharply decreased with effective metformin pretreatments in ischemic brains. Our data provided the first evidence that in acute ischemic injury, a 7-days pretreatment duration of 10 mg/kg metformin is necessary for its neuroprotection, and metformin may not be beneficial in the cases of blood reperfusion.

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain.

BACKGROUND: It is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain. METHODS: Neuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC(-/-) (histidine decarboxylase gene knockout) and IL-1R(-/-) (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1ß production, respectively. RESULTS: Histidine (100 mg/kg, i.p.) administered throughout days 0-3, 0-7, or 0-14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2-3, 4-7, and 8-14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1ß upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC(-/-) mice and IL-1R(-/-) mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia. CONCLUSIONS: These results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1ß production in the spinal cord following nerve injury.

Oral Administration of Pregabalin in Rats before or after Nerve Injury Partially Prevents Spontaneous Neuropathic Pain and Long Outlasts the Treatment Period.

BACKGROUND AND METHODS: Pregabalin alleviates stimulus-evoked neuropathic pain (NeuP) in some pain patients and rodents in models of painful neuropathies. But it is not known if pregabalin can also alleviate spontaneous NeuP. Sciatic and saphenous neurectomy in rats elicits spontaneous self-mutilation of the denervated hindpaw, a behavior that models spontaneous NeuP. We tested if pregabalin (20 or 30 mg/kg/day; twice daily, per os) for 7 days before denervation, or 42 days thereafter, can suppress this behavior. RESULTS: Compared with the vehicle, pregabalin administered in both treatment regimens markedly and significantly delayed autotomy onset and suppressed its levels for weeks after treatment cessation. CONCLUSIONS: At doses known to effectively suppress stimulus-evoked pain in rats, pregabalin can prevent development of spontaneous NeuP and suppress it postoperatively.

Widespread pain sensitization after partial infraorbital nerve transection in MRL/MPJ mice.

Clinical studies show that chronic pain can spread to adjacent or even distant body regions in some patients. However, little is known about how this happens. In this study, we found that partial infraorbital nerve transection (p-IONX) in MRL/MPJ mice induced not only marked and long-lasting orofacial thermal hyperalgesia but also thermal hyperalgesia from day 3 postoperatively (PO) and tactile allodynia from day 7 PO in bilateral hind paws. Pain sensitization in the hind paw was negatively correlated with facial thermal hyperalgesia at early but not late stage after p-IONX. After a rapid activation of c-Fos, excitability and excitatory synaptic neurotransmission in lumbar dorsal horn neurons were elevated from day 3 and day 7 PO, respectively. In addition, microglial activation after p-IONX transmitted caudally from the Vc in the medulla to lumber dorsal horn in a time-dependent manner. Inhibition of microglial activation by minocycline at early but not late stage after p-IONX postponed and attenuated pain sensitization in the hind paw. These results indicate that neuropathic pain after p-IONX in MRL/MPJ mice spreads from the orofacial region to distant somatic regions and that a rostral-caudal transmission of central sensitization in the spinal cord is involved in the spreading process of pain hypersensitivity.

[Antiepileptic effect of low-frequency electrical stimulation is waveform-dependent in hippocampal kindled mice].

OBJECTIVE: To investigate whether the waveform of electrical stimulus affects the antiepileptic effect of focal low-frequency stimulation (LFS). METHODS: The antiepileptic effects of the LFS in sine, monophase square and biphase square waves were investigated in hippocampal kindled mice, respectively. RESULTS: Compared to the control group, sine wave focal LFS (30 s) inhibited seizure stages (2.85 ± 0.27 vs 4.75 ± 0.12, P<0.05), lowered incidence of generalized seizures (53.6% vs 96.5%, P<0.01) and reduced afterdischarge durations [(16.2 2 ± 1.69)s vs (30.29 ± 1.12)s, P<0.01] in hippocampal kindled mice, while monophase or biphase square wave LFS (30 s) showed no antiepileptic effect. Monophase square LFS (15 min) inhibited seizure stages (3.58 ± 0.16, P<0.05) and incidence of generalized seizures (66.7%,P<0.01), but had weaker inhibitory effect on hippocampal afterdischarge durations than sine wave LFS. In addition, pre-treatment and 3 s but not 10 s post-treatment with sine wave LFS resulted in suppression of evoked seizures (P<0.05 or P<0.01). CONCLUSION: The antiepileptic effect of LFS is dependent on its waveform. Sine wave may be optimal for closed-loop LFS treatment of epilepsy.

Early treatment of minocycline alleviates white matter and cognitive impairments after chronic cerebral hypoperfusion.

Subcortical ischemic vascular dementia (SIVD) caused by chronic cerebral hypoperfusion develops with progressive white matter and cognitive impairments, yet no effective therapy is available. We investigated the temporal effects of minocycline on an experimental SIVD exerted by right unilateral common carotid arteries occlusion (rUCCAO). Minocycline treated at the early stage (day 0-3), but not the late stage after rUCCAO (day 4-32) alleviated the white matter and cognitive impairments, and promoted remyelination. The actions of minocycline may not involve the inhibition of microglia activation, based on the effects after the application of a microglial activation inhibitor, macrophage migration inhibitory factor, and co-treatment with lipopolysaccharides. Furthermore, minocycline treatment at the early stage promoted the proliferation of oligodendrocyte progenitor cells (OPCs) in subventricular zone, increased OPC number and alleviated apoptosis of mature oligodendrocytes in white matter. In vitro, minocycline promoted OPC proliferation and increased the percentage of OPCs in S and G2/M phases. We provided direct evidence that early treatment is critical for minocycline to alleviate white matter and cognitive impairments after chronic cerebral hypoperfusion, which may be due to its robust effects on OPC proliferation and mature oligodendrocyte loss. So, early therapeutic time window may be crucial for its application in SIVD.

Protective effect of carnosine on febrile seizures in immature mice.

Febrile seizures (FSs) are the most common type of convulsions in childhood and complex FSs represent an increased risk for development of temporal lobe epilepsy. The aim of this study was to analyze the anticonvulsant effects of carnosine, an endogenous dipeptide composed of alanine and histidine, on hyperthermia induced seizure in immature mice. Injection of carnosine significantly increased the latency and decreased the duration of FSs in a dose-dependent manner. In addition, histidine had similar effects on FSs as carnosine. The protective effect of carnosine or histidine was completely abolished by α-fluoromethylhistidine (α-FMH), a selective and irreversible histidine decarboxylase inhibitor, or in histidine decarboxylase deficient (HDC-KO) mice. Peripheral carnosine administration increased the level of carnosine, histidine and histamine in the cortex and hippocampus of mice pups, but decreased glutamate contents in the cortex and hippocampus. These results indicate that carnosine can protect against FSs in mice pups through its conversion to histamine, suggesting that it may serve as an efficient anti-FSs drug in the future.

Endoplasmic reticulum stress induced by tunicamycin and thapsigargin protects against transient ischemic brain injury: Involvement of PARK2-dependent mitophagy.

Transient cerebral ischemia leads to endoplasmic reticulum (ER) stress. However, the contributions of ER stress to cerebral ischemia are not clear. To address this issue, the ER stress activators tunicamycin (TM) and thapsigargin (TG) were administered to transient middle cerebral artery occluded (tMCAO) mice and oxygen-glucose deprivation-reperfusion (OGD-Rep.)-treated neurons. Both TM and TG showed significant protection against ischemia-induced brain injury, as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue. In OGD-Rep.-treated neurons, 4-PBA, the ER stress releasing mechanism, counteracted the neuronal protection of TM and TG, which also supports a protective role of ER stress in transient brain ischemia. Knocking down the ER stress sensor Eif2s1, which is further activated by TM and TG, reduced the OGD-Rep.-induced neuronal cell death. In addition, both TM and TG prevented PARK2 loss, promoted its recruitment to mitochondria, and activated mitophagy during reperfusion after ischemia. The neuroprotection of TM and TG was reversed by autophagy inhibition (3-methyladenine and Atg7 knockdown) as well as Park2 silencing. The neuroprotection was also diminished in Park2(+/-) mice. Moreover, Eif2s1 and downstream Atf4 silencing reduced PARK2 expression, impaired mitophagy induction, and counteracted the neuroprotection. Taken together, the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury. The PARK2-mediated mitophagy may be underlying the protection of ER stress. These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through ER stress activation.

Histamine upregulates Nav1.8 expression in primary afferent neurons via H2 receptors: involvement in neuropathic pain.

INTRODUCTION: The upregulation of Nav1.8 in primary afferents plays a critical role in the development and persistence of neuropathic pain. The mechanisms underlying the upregulation are not fully understood. AIMS: The present study aims to investigate the regulatory effect of histamine on the expression of Nav1.8 in primary afferent neurons and its involvement in neuropathic pain. RESULTS: Histamine at 10(-8) M increased the expression of Nav1.8 in cultured DRG neurons. This effect could be blocked by H2 receptor antagonist cimetidine or famotidine, but not by H1 receptor antagonist pyrilamine or dual H3 /H4 antagonist thioperamide. Peri-sciatic administration of histamine increased Nav1.8 expression in the sciatic nerve and L4/L5 DRG neurons in a dose-dependent manner, accompanied with remarkable mechanical allodynia and heat hyperalgesia in the ipsilateral hindpaw. Famotidine but not pyrilamine or thioperamide inhibited Nav1.8 upregulation and pain hypersensitivity. In addition, famotidine (40 mg/kg, i.p.) not only suppressed autotomy behavior in the rat neuroma model of neuropathic pain but also attenuated mechanical allodynia and thermal hyperalgesia following partial sciatic nerve ligation. Moreover, famotidine inhibited Nav1.8 upregulation in the neuroma and ligated sciatic nerve. CONCLUSIONS: Our findings indicate that histamine increases Nav1.8 expression in primary afferent neurons via H2 receptor-mediated pathway and thereby contributes to neuropathic pain. H2 receptor antagonists may potentially be used as analgesics for patients with neuropathic pain.

A novel neuroprotective strategy for ischemic stroke: transient mild acidosis treatment by CO2 inhalation at reperfusion.

Acidosis is one of the key components in cerebral ischemic postconditioning that has emerged recently as an endogenous strategy for neuroprotection. We set out to test whether acidosis treatment at reperfusion can protect against cerebral ischemia/reperfusion injury. Adult male C57BL/6 J mice were subjected to 60-minute middle cerebral arterial occlusion followed by 24-hour reperfusion. Acidosis treatment by inhaling 10%, 20%, or 30% CO2 for 5 or 10 minutes at 5, 50, or 100 minutes after reperfusion was applied. Our results showed that inhaling 20% CO2 for 5 minutes at 5 minutes after reperfusion-induced optimal neuroprotection, as revealed by reduced infarct volume. Attenuating brain acidosis with NaHCO3 significantly compromised the acidosis or ischemic postconditioning-induced neuroprotection. Consistently, both acidosis-treated primary cultured cortical neurons and acute corticostriatal slices were more resistant to oxygen-glucose deprivation/reperfusion insult. In addition, acidosis inhibited ischemia/reperfusion-induced apoptosis, caspase-3 expression, cytochrome c release to cytoplasm, and mitochondrial permeability transition pore (mPTP) opening. The neuroprotection of acidosis was inhibited by the mPTP opener atractyloside both in vivo and in vitro. Taken together, these findings indicate that transient mild acidosis treatment at reperfusion protects against cerebral ischemia/reperfusion injury. This neuroprotection is likely achieved, at least partly, by inhibiting mPTP opening and mitochondria-dependent apoptosis.

[Protective effects of beraprost plus simvastatin on monocrotaline-induced pulmonary arterial hypertension in rats].

OBJECTIVE: To explore the protective effects of beraprost plus simvastatin on monocrotaline-induced pulmonary arterial hypertension in rats. METHODS: Forty male Sprague-Dawley rats were allocated to control (C), untreated pulmonary arterial hypertension (P), beraprost (B), simvastatin (S) and combination groups (Com) (n = 8 each). Normal saline was injected subcutaneously into group C and then there was no other intervention for 21 days. Group P, B, S and Com rats received subcutaneous injections of monocrotaline (MCT, 60 mg/kg) and then isovolumetric normal saline, beraprost (100 µg·kg(-1)·d(-1)), simvastatin (2 mg·kg(-1)·d(-1)) and beraprost (100 µg·kg(-1)·d(-1)) plus simvastatin (2 mg·kg(-1)·d(-1)) by daily gastric lavage for 21 days. At Day 22, heart rate (HR), mean arterial pressure (MAP) and mean pulmonary pressure (mPAP) were detected and right heart ventricular hypertrophy index (RVHI) was calculated. The histopathology changes and tunica media thickness percentage of pulmonary arteries (WT%) were evaluated by pulmonary tissue staining. The results were analyzed statistically. RESULTS: The differences of HR and MAP were not significant among 5 groups (all P > 0.05). The levels of mPAP, RVHI and WT% in group B ((27.4 ± 3.7) mm Hg, 0.35 ± 0.03, 26.7% ± 2.4%), group S ((29.9 ± 4.4) mm Hg, 0.36 ± 0.03, 28.2% ± 1.9%) and group Com ((23.1 ± 3.9) mm Hg, 0.32 ± 0.03, 17.4% ± 3.3%) were lower than those in group P ((35.4 ± 5.7) mm Hg, 0.41 ± 0.05, 42.8% ± 5.9%) (all P < 0.05). CONCLUSIONS: The combined use of beraprost and simvastatin may delay the increase of mPAP and remodeling of pulmonary vessels and inhibit right ventricular hypertrophy in pulmonary arterial hypertension rats. Its efficacy is superior to that of monotherapy.

Histamine modulation of acute nociception involves regulation of Nav 1.8 in primary afferent neurons in mice.

AIMS: To explore the role of histamine in acute pain perception and its possible mechanisms. METHODS: Pain-like behaviors induced by four types of noxious stimuli (hot-plate, tail-pressure, acetic acid, and formalin) were accessed in mice. Nav 1.8 expression and functions in primary afferent neurons were compared between histidine decarboxylase knockout (HDC(-/-) ) mice and their wild-types. RESULTS: HDC(-/-) mice, lacking in endogenous histamine, showed elevated sensitivity to all these noxious stimuli, as compared with the wild-types. In addition, a depletion of endogenous histamine with α-fluoromethylhistidine (α-FMH), a specific HDC inhibitor, or feeding mice a low-histamine diet also enhanced nociception in the wild-types. Nav 1.8 expression in primary afferent neurons was increased both in HDC(-/-) and in α-FMH-treated wild-type mice. A higher Nav 1.8 current density, a lower action potential (AP) threshold, and a higher firing rate in response to suprathreshold stimulation were observed in nociception-related small DRG neurons of HDC(-/-) mice. Nav 1.8 inhibitor A-803467, but not TTX, diminished the hyperexcitability and blocked repetitive AP firing of these neurons. CONCLUSION: Our results indicate that histamine participates in acute pain modulation in a dose-related manner. The regulation of Nav 1.8 expression and the excitability of nociceptive primary afferent neurons may be involved in the underlying mechanisms.

Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults.

Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke.

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy.

The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC(-/-)) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 µg/5 µL) significantly suppressed autotomy behavior in rats. HDC(-/-) mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.