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Chen Zhi-wu - One of the best experts on this subject based on the ideXlab platform.
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Cardioprotective effect of Intracerebroventricular morphine preconditioning on myocardial postischemia injury is mediated by adenosine receptor in spinal cord
Chinese Pharmacological Bulletin, 2010Co-Authors: Chen Zhi-wuAbstract:Aim To investigate whether the protective effect of Intracerebroventricular morphine preconditioning to myocardial is mediated by adenosine receptor in spinal cord,and the relationship with the inflammatory reaction of ischemia-reperfusion injury. Methods Rats with intrathecal and Intracerebroventricular Catheter placement were randomly assigned to 5 groups: Sham group,control group,MPC group,MPC + THE group and THE group. Indicators to be observed were composed of MAP,HR and RPP ( MAP × HR) ; in-farct size ( IS) ,as a percentage of the area at risk,was determined by 2,3,5-triphenyltetrazolium staining,the volume of area at risk ( AAR) ,and the area of myocardial infarction,which was demonstrated by IS/AAR. And also the ICAM-1 expression in myocardium was determined by immunohistochemical method. Result Compared with the control group,the volume of IS and IS/AAR both declined in MPC group and MPC + THE group ( P 0. 01) ,but the volume of IS and IS/AAR of MPC + THE group was higher than that of MPC group( P 0. 01) . There was no significant difference between THE group and the control group( P 0. 05) . ICAM-1 expression in myocardium of the control group was higher than those of Sham group,MPC group and MPC + THE group. ( P 0. 01) . Compared with MPC group,ICAM-1 expressed in myocardium of MPC + THE group was much more( P 0. 01) . Conclusion Intracerebroventricular morphine can up-regulate the activation of adenosine receptor in spinal cord. The latter suppresses the inflammatory reaction of ischemia-reperfusion injury,and partly mediates the cardioprotective effect of Intracerebroventricular morphine preconditioning this way.
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Effects of Intracerebroventricular morphine preconditioning on expression of calmodulin in hippocampus,calcitonin gene related peptide in plasma,substance P in hypothalamic paraventricular nucleus and myocardium in myocardial postischemia injury rats
Chinese Pharmacological Bulletin, 2009Co-Authors: Chen Zhi-wuAbstract:Aim To investigate the protective effect of Intracerebroventricular morphine preconditioning to myocardial ischemia/reperfusion injury in intact rat heart and the mechanism of this cardioprotection.Methods Rats were established Intracerebroventricular Catheter placement and myocardial ischemia/reperfusion models randomly assigned to two series:① four groups: control group(CON);Intracerebroventricular morphine preconditioning group(MPC);trifluoperazine,a calmodulin antagonist Intracerebroventricular 10 min before Intracerebroventricular morphine(TFP+MPC) and itself control(TFP).② three groups: Sham group(Sham),CON and MPC.Indicators to be observed were composed of MAP,HR and RPP(MAP×HR);the volume of area at risk(AAR),infarct size(IS) and the area of myocardial infarction,were demonstrated by IS/AAR.Meanwhile,the CGRP in the blood plasma was tested by radioimmunity protocol.The epression of calmodulin in the hippocampus was determined by Western blot.Expressions of SP in the hypothalamic paraventricular nucleus,ischemia and non-ischemia myocardium area were determined by immunohistochemical method.Results Compared with other groups,the volume of IS and IS/AAR reduced in MPC group(P0.01);the calcitonin gene related peptide(CGRP) in the blood plasma and expression of calmodulin in the hippocampus were higher than that of other groups(P0.01).Compared with CON group,integrated optical density of SP in MPC group expressed in paraventricular hypothalamic nucleus,ischemia and non-ischemia myocardial were lower(P0.01,P0.05).Conclusions Intracerebroventricular morphine preconditioning can produce cardioprotective effect against ischemia/reperfusion injury,which involves in CGRP mediated by calmodulin in hippocampus and also associated with analgesia.
Stephen M. Strittmatter - One of the best experts on this subject based on the ideXlab platform.
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Delayed Nogo receptor therapy improves recovery from spinal cord contusion
Annals of Neurology, 2006Co-Authors: Xingxing Wang, Kenneth W. Baughman, D. Michele Basso, Stephen M. StrittmatterAbstract:When the adult mammalian central nervous system is injured, severed axons from surviving neurons do not extend and reconnect to their synaptic targets.1–4 The resulting axonal disconnection constitutes a significant cause of persistent neurological deficits in many neurological conditions. Traumatic spinal cord injury (SCI) is perhaps the purest example of a disconnection-based syndrome secondary to failed axonal growth. Although focal neuronal loss contributes to segmental dysfunction at the level of injury after SCI, chronic neurological deficits below the level of injury are principally due to the failure of axonal regrowth. Recent laboratory studies have identified three myelin-associated proteins, Nogo-A, Myelin-Associated Protein (MAG), and Oligodendrocyte Myelin Glycoprotein (OMgp), which bind to an axonal Nogo-66 receptor (NgR) protein to collapse axonal growth cones and stop axonal extension.1,5–13 The importance of this pathway has been documented in a range of genetic and pharmacological studies in rodent SCI. Pharmacological studies have used peptides that competitively inhibit Nogo-66 interaction with NgR,14,15 anti–Nogo-A antibodies,16,17 and a soluble ectodomain fragment of the NgR.2,18–20 The NgR fragment fused to the constant region of IgG in the NgR(310)ecto-Fc reagent contains the entire ligand-binding site of NgR. Thus, this fragment can sequester all three myelin-associated inhibitors from active endogenous axonal NgR. When infused intrathecally into rats with midthoracic dorsal spinal hemisection injuries, the NgR(310)ecto-Fc protein stimulates corticospinal tract (CST) and raphespinal axonal growth.19 Critically, the recovery of locomotor performance was stimulated by NgR(310)ecto-Fc. A group of recent studies have generated interest in the notion that intracellular cyclic adenosine mono-phosphate (cAMP) levels play a role in determining the propensity of neurons to extend axons. In particular, elevated cAMP levels reduce inhibition by myelin-associated proteins in vitro.21–25 Several combinatorial therapies to promote axonal growth and functional recovery after for including a method for increasing cAMP.21,22 Ro- lipram is a type VI cyclic nucleotide phosphodiesterase inhibitor most commonly used in axonal regeneration experiments. An extrapolation of the benefits of blocking myelin-associated inhibitors to human SCI is limited by two factors. First, the experimental studies have focused on simplified transection models of SCI that do not include the complex inflammatory and hemorrhagic tissue reaction that occurs in typical clinical injuries caused by abrupt contusion from displaced vertebral bodies. Second, most previous experiments using simple transection studies have initiated therapy at the time of injury. As is clear from numerous studies of stroke, the benefits of immediate therapy are not always translatable to the clinic. Here, we determined whether blocking myelin-associated inhibitors with NgR(310)ecto-Fc is effective under conditions thought to be most similar to those encountered clinically. The recovery of rats from spinal contusion injury was assessed.26 Treatment was initiated by intrathecal spinal Catheter at the time of injury or was provided by an Intracerebroventricular Catheter beginning at 3 days after injury. Furthermore, a combination of rolipram and NgR(310)ecto-Fc was compared with monotherapy. We report that NgR(310)ecto-Fc substantially improves locomotor recovery. This recovery is associated with CST and raphespinal axonal growth. Rolipram is less effective and is not synergistic with NgR(310)ecto-Fc. These findings provide a rationale for investigating the benefit of NgR(310)ecto-Fc therapy in human SCI.
Yasemin Burcu Üstün - One of the best experts on this subject based on the ideXlab platform.
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Intracerebroventricular Application of Dexmedetomidine Produces Antinociception and Does not Cause Neurotoxicity in Rats
Balkan medical journal, 2013Co-Authors: Ersin Köksal, Deniz Karakaya, Bilge Can, Ayhan Bozkurt, Sibel Barış, Süleyman Sırrı Bilge, Yasemin Burcu ÜstünAbstract:Background: Alpha2 agonists contribute to pain control at the level of the medulla spinalis. Alpha2 agonists are generally added to local anaesthetics to prolong spinal or epidural anaesthesia time. Aims: In the present study, we aimed to evaluate the antinociceptive and neurotoxic effects of dexmedetomidine given Intracerebroventricularly for 5 days. Study Design: Animal experimentation. Methods: After intraventricular cannulation, rats (n=32) were divided into two groups (n=16 each). Rats in the dexmedetomidine group (Group D, n=16) received 3 mg (0.03 mL) dexmedetomidine and the control group (Group C, n=16) received 0.03 mL physiological serum through an Intracerebroventricular Catheter once a day, for 5 days. Antinociceptive, sedative, and motor effects were evaluated before the injection and for 90 min after injection. The tail-flick and hot plate tests were used to assess thermal nociceptive threshold. For histopathological evaluation, half of the rats in both groups were sacrificed on the 6th day and the remaining rats were sacrificed on the 21st day. Then the perfusion fixation method was applied. The first tissue section was obtained from the cervical spinal cord 1 cm distal to the proximal end of the spinal cord. The second sample was retrieved from the region 1 cm distal from the thoracic 13-lumbar 1 vertebra. On morphological evaluation, nonspecific changes like edema and gliosis, signs of neuronal degeneration demonstrating a severe reaction, and density of inflammatory cells were examined. Results: In dexmedetomidine-administered rats, on the first day reaction times at 5, 10, and 20 min and on the other days, reaction times at 5, 10, 20, and 30 min in hot plate tests were significantly longer compared with baseline values (pl0.05). In dexmedetomidine-administered rats, on the 1st, 4th, and 5th days reaction times at 5, 10, 20, 30, and 40 min and on the 2nd and 3rd days reaction times at 5, 10, 20, and 30 min in tail-flick tests were significantly longer compared with baseline values (pl0.05). First-degree sedation lasting for 60 min and first-degree motor block lasting for 30n40 min were observed in the dexmedetomidine group. Similar rates of nonspecific changes such as edema and gliosis were seen in both groups. Signs of severe reactions such as neuronal degeneration and diffuse inflammatory cell infiltration were not encountered in any group. There was no significant difference between groups according to morphological findings of the spinal cord on the 6th and 21st days (pg0.05). Conclusion: We observed that Intracerebroventricular administration of 3 mg dexmedetomidine produced antinociception and did not cause neurotoxicity. Turkish Baslik:: Intraserebroventrikuler Deksmedetomidin Uygulamasi Ratlarda Antinosisepsiyon Saglar ve Norotoksisiteye Neden Olmaz Anahtar Kelimeler:Deksmedetomidin, antinosisepsiyon, norotoksisite Arkaplan: Alfa2 agonistler medulla spinalis seviyesinde agri kontrolune katkida bulunurlar. Spinal veya epidural anestezi suresini uzatmak amaciyla alfa2 agonistler siklikla lokal anestezik ajanlara ilave edilmektedir. Amac: Biz bu calismada; deksmedetomidini intraserebroventrikuler yoldan bes gun boyunca uygulayarak antinosiseptif ve norotoksik etkisini arastirmayi amacladik. Calisma Tasarimi: Paralel deneysel calisma. Yontemler: Intraventrikuler kanulasyon sonrasi ratlar (n=32) iki gruba ayrildi. Deksmedetomidin grubundaki ratlara (n=16) 3 mg (0.03 mL) dekmedetomidin ve kontrol grubundakilere (n=16) 0.03 mL serum fizyolojik intraventrikuler kateter yoluyla gunde bir kez olacak sekilde 5 gun boyunca uygulandi. Antinosiseptf, sedatif ve motor etkiler enjeksiyon oncesi ve 90 dakika boyunca degerlendirildi. Analjezik etkinligi degerlendirmek icin kuyruk batirma ve sicak zemin testleri kullanildi. Histopatolojik degerlendirme icin her iki gruptaki ratlarin yarisi 6. gunde, kalan ratlar 21. gunde sakrifiye edildi ve perfuzyon fiksasyon uygulandi. Doku kesitlerinden birincisi spinal kordun baslangicinin 1 cm distalindeki servikal spinal korddan alindi. Ikincisi ise torakal 13-lomber 1 seviyesinin 1 cm distalindeki lomber bolgeden alindi. Morfolojik degerlendirmede odem, gliozis gibi nonspesifik degisiklikler ve siddetli reaksiyonu gosteren noronal dejenerasyon bulgulari ve inflamatuvar hucre yogunlugu degerlendirildi. Bulgular: Deksmedetomidin uygulanan ratlarda, sicak zemin testinde ilk gun 5., 10., 20. dakikalardaki ve diger gunlerde 5., 10., 20., 30. dakikalardaki reaksiyon zamanlari bazal degerler ile karsilastirildiginda anlamli olarak uzun bulundu (pl0.05). Deksmedetomidin uygulanan ratlarda, kuyruk batirma testinde 1.,4., ve 5. gunlerde 5., 10., 20., 30., 40. dakikalardaki ve 2., ve 3. gunlerde 5., 10., 20., 30. dakikalardaki reaksiyon zamanlari bazal degerler ile karsilastirildiginda anlamli olarak uzun bulundu (pl0.05). Dekmedetomidin grubunda 60 dakika devam eden birinci derece sedasyon ve 30-40 dakika devam eden birinci derece motor blok gozlemledik. Her iki grupta da odem ve gliozis gibi nonspesifik degisiklikler benzer oranda goruldu. Noronal dejenerasyon ve inflamatuvar hucre yogunlugunu iceren siddetli reaksiyon bulgularina her iki grupta da rastlanmadi. Spinal kordun morfolojik incelemesinde 6. ve 21. gunlerdeki degerlendirmede de gruplar arasinda histopatolojik anlamli fark bulunamadi (pg0.05). Sonuc: Intraserebroventrikuler yoldan uygulanan 3 mg deksmedetomidin antinosiseptif etkinlik gosterir ve norotoksisiteye neden olmaz.
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Intracerebroventricular Application of Dexmedetomidine Produces Antinociception and Does not Cause Neurotoxicity in Rats
Galenos Publishing House, 2013Co-Authors: Ersin Köksal, Deniz Karakaya, Bilge Can, Ayhan Bozkurt, Sibel Barış, Süleyman Sırrı Bilge, Yasemin Burcu ÜstünAbstract:Background: Alpha2 agonists contribute to pain control at the level of the medulla spinalis. Alpha2 agonists are generally added to local anaesthetics to prolong spinal or epidural anaesthesia time. Aims: In the present study, we aimed to evaluate the antinociceptive and neurotoxic effects of dexmedetomidine given Intracerebroventricularly for 5 days. Study Design: Animal experimentation. Methods: After intraventricular cannulation, rats (n=32) were divided into two groups (n=16 each). Rats in the dexmedetomidine group (Group D, n=16) received 3 µg (0.03 mL) dexmedetomidine and the control group (Group C, n=16) received 0.03 mL physiological serum through an Intracerebroventricular Catheter once a day, for 5 days. Antinociceptive, sedative, and motor effects were evaluated before the injection and for 90 min after injection. The tail-flick and hot plate tests were used to assess thermal nociceptive threshold. For histopathological evaluation, half of the rats in both groups were sacrificed on the 6th day and the remaining rats were sacrificed on the 21st day. Then the perfusion fixation method was applied. The first tissue section was obtained from the cervical spinal cord 1 cm distal to the proximal end of the spinal cord. The second sample was retrieved from the region 1 cm distal from the thoracic 13-lumbar 1 vertebra. On morphological evaluation, nonspecific changes like edema and gliosis, signs of neuronal degeneration demonstrating a severe reaction, and density of inflammatory cells were examined. Results: In dexmedetomidine-administered rats, on the first day reaction times at 5, 10, and 20 min and on the other days, reaction times at 5, 10, 20, and 30 min in hot plate tests were significantly longer compared with baseline values (p
Takahiko Hayashi - One of the best experts on this subject based on the ideXlab platform.
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Effect of the NMDA-antagonist, MK 801, on benzodiazepine-opioid interactions at the spinal and supraspinal level in rats.
British journal of pharmacology, 1995Co-Authors: T. J. Luger, Ingo H. Lorenz, Christina Grabner-weiss, Takahiko HayashiAbstract:1. Benzodiazepines potentiate morphine antinociception at the spinal level via GABAergic mechanisms. At the supraspinal level, the inhibitory effect of midazolam on morphine antinociception cannot be easily explained by GABAA receptor activation. Since excitatory amino acids play a role in central transmission, we investigated the effect of dizocilpine (MK 801) on this interaction in spinal cord and brain. 2. In rats with an intrathecal or Intracerebroventricular Catheter, the mechanisms of the antinociceptive effect of benzodiazepine-morphine combinations were tested during thermal nociceptive tests. 3. The principal findings of this study were that at the spinal level, midazolam potentiation of morphine antinociception can be antagonized by the NMDA antagonist, MK 801 (10 micrograms), as assessed by hot-plate and tail-flick tests. When drugs were administered supraspinally, midazolam inhibited morphine antinociception only in the hot-plate test, an effect also inhibited by MK 801. In the tail-flick assay, midazolam failed to influence the morphine response. 4. The NMDA antagonist significantly affected midazolam antinociception at the spinal level, but was not effective following i.c.v. administration of the drugs. MK 801 had no effect on morphine antinociception after i.t. and i.c.v. administration of the drugs. 5. The paradoxical effect of midazolam on morphine antinociception and its reversal by MK 801 might be due to modulation at various levels of the neuraxis and/or modulation of different pathways mediated via both GABAA and NMDA receptor mechanisms.
Xingxing Wang - One of the best experts on this subject based on the ideXlab platform.
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Delayed Nogo receptor therapy improves recovery from spinal cord contusion
Annals of Neurology, 2006Co-Authors: Xingxing Wang, Kenneth W. Baughman, D. Michele Basso, Stephen M. StrittmatterAbstract:When the adult mammalian central nervous system is injured, severed axons from surviving neurons do not extend and reconnect to their synaptic targets.1–4 The resulting axonal disconnection constitutes a significant cause of persistent neurological deficits in many neurological conditions. Traumatic spinal cord injury (SCI) is perhaps the purest example of a disconnection-based syndrome secondary to failed axonal growth. Although focal neuronal loss contributes to segmental dysfunction at the level of injury after SCI, chronic neurological deficits below the level of injury are principally due to the failure of axonal regrowth. Recent laboratory studies have identified three myelin-associated proteins, Nogo-A, Myelin-Associated Protein (MAG), and Oligodendrocyte Myelin Glycoprotein (OMgp), which bind to an axonal Nogo-66 receptor (NgR) protein to collapse axonal growth cones and stop axonal extension.1,5–13 The importance of this pathway has been documented in a range of genetic and pharmacological studies in rodent SCI. Pharmacological studies have used peptides that competitively inhibit Nogo-66 interaction with NgR,14,15 anti–Nogo-A antibodies,16,17 and a soluble ectodomain fragment of the NgR.2,18–20 The NgR fragment fused to the constant region of IgG in the NgR(310)ecto-Fc reagent contains the entire ligand-binding site of NgR. Thus, this fragment can sequester all three myelin-associated inhibitors from active endogenous axonal NgR. When infused intrathecally into rats with midthoracic dorsal spinal hemisection injuries, the NgR(310)ecto-Fc protein stimulates corticospinal tract (CST) and raphespinal axonal growth.19 Critically, the recovery of locomotor performance was stimulated by NgR(310)ecto-Fc. A group of recent studies have generated interest in the notion that intracellular cyclic adenosine mono-phosphate (cAMP) levels play a role in determining the propensity of neurons to extend axons. In particular, elevated cAMP levels reduce inhibition by myelin-associated proteins in vitro.21–25 Several combinatorial therapies to promote axonal growth and functional recovery after for including a method for increasing cAMP.21,22 Ro- lipram is a type VI cyclic nucleotide phosphodiesterase inhibitor most commonly used in axonal regeneration experiments. An extrapolation of the benefits of blocking myelin-associated inhibitors to human SCI is limited by two factors. First, the experimental studies have focused on simplified transection models of SCI that do not include the complex inflammatory and hemorrhagic tissue reaction that occurs in typical clinical injuries caused by abrupt contusion from displaced vertebral bodies. Second, most previous experiments using simple transection studies have initiated therapy at the time of injury. As is clear from numerous studies of stroke, the benefits of immediate therapy are not always translatable to the clinic. Here, we determined whether blocking myelin-associated inhibitors with NgR(310)ecto-Fc is effective under conditions thought to be most similar to those encountered clinically. The recovery of rats from spinal contusion injury was assessed.26 Treatment was initiated by intrathecal spinal Catheter at the time of injury or was provided by an Intracerebroventricular Catheter beginning at 3 days after injury. Furthermore, a combination of rolipram and NgR(310)ecto-Fc was compared with monotherapy. We report that NgR(310)ecto-Fc substantially improves locomotor recovery. This recovery is associated with CST and raphespinal axonal growth. Rolipram is less effective and is not synergistic with NgR(310)ecto-Fc. These findings provide a rationale for investigating the benefit of NgR(310)ecto-Fc therapy in human SCI.