Neuroprotective effects of a new synthetic peptide, CMX-9236, in in vitro and in vivo models of cerebral ischemia

The role of brain insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) in neuroprotection was further investigated using in vitro and in vivo models of cerebral ischemia by assessing the effects of IGF-I, IGF-II, and high affinity IGFBP ligand inhibitors (the peptide [Leu24, 59, 60, Ala31]hIGF-I (IGFBP-LI) and the small molecule NBI-31772 (1-(3,4-dihydroxybenzoyl)-3-hydroxycarbonyl-6, 7-dihydroxyisoquinoline), which pharmacologically displace and elevate endogenous, bioactive IGFs from IGFBPs. Treatment with IGF-I, IGF-II, or IGFBP-LI (2 μg/mL) significantly ( P < 0.05) reduced CA1 damage in organotypic hippocampal cultures resulting from 35 minutes of oxygen and glucose deprivation by 71%, 60%, and 40%, respectively. In the subtemporal middle cerebral artery occlusion (MCAO) model of focal ischemia, intracerebroventricular (icv) administration of IGF-I and IGF-II at the time of artery occlusion reduced ischemic brain damage in a dose-dependent manner, with maximum reductions in total infarct size of 37% ( P < 0.01) and 38% ( P < 0.01), respectively. In this model of MCAO, icv administration of NBI-31772 at the time of ischemia onset also dose-dependently reduced infarct size, and the highest dose (100 μg) significantly reduced both total (by 40%, P < 0.01) and cortical (by 43%, P < 0.05) infarct volume. In the intraluminal suture MCAO model, administration of NBI-31772 (50 μg icv) at the time of artery occlusion reduced both cortical infarct volume (by 40%, P < 0.01) and brain swelling (by 24%, P < 0.05), and it was still effective when treatment was delayed up to 3 hours after the induction of ischemia. These results further define the neuroprotective properties of IGFs and IGFBP ligand inhibitors in experimental models of cerebral ischemia.

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Neuroprotective effects of a novel water-soluble poly(ADP-ribose) polymerase-1 inhibitor, MP-124, in in vitro and in vivo models of cerebral ischemia

Brain Research ◽

10.1016/j.brainres.2011.03.031 ◽

2011 ◽

Vol 1389 ◽

pp. 169-176 ◽

Cited By ~ 16

Author(s):

Yasuhiro Egi ◽

Shigeru Matsuura ◽

Tomoyuki Maruyama ◽

Masakazu Fujio ◽

Satoshi Yuki ◽

...

Keyword(s):

Cerebral Ischemia ◽

Water Soluble ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Soluble Poly

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In Vitro and In Vivo Models of Cerebral Ischemia Show Discrepancy in Therapeutic Effects of M2 Macrophages

PLoS ONE ◽

10.1371/journal.pone.0067063 ◽

2013 ◽

Vol 8 (6) ◽

pp. e67063 ◽

Cited By ~ 31

Author(s):

Virginie Desestret ◽

Adrien Riou ◽

Fabien Chauveau ◽

Tae-Hee Cho ◽

Emilie Devillard ◽

...

Keyword(s):

Cerebral Ischemia ◽

Therapeutic Effects ◽

M2 Macrophages ◽

In Vivo Models

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ROS-Dependent Neuroprotective Effects of NaHS in Ischemia Brain Injury Involves the PARP/AIF Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000430317 ◽

2015 ◽

Vol 36 (4) ◽

pp. 1539-1551 ◽

Cited By ~ 35

Author(s):

Qian Yu ◽

Zhihong Lu ◽

Lei Tao ◽

Lu Yang ◽

Yu Guo ◽

...

Keyword(s):

Brain Injury ◽

Focal Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Dependent Manner ◽

Neuroprotective Effects ◽

Ht22 Cells ◽

In Vivo Models ◽

The Brain

Background/Aims: Stroke is among the top causes of death worldwide. Neuroprotective agents are thus considered as potentially powerful treatment of stroke. Methods: Using both HT22 cells and male Sprague-Dawley rats as in vitro and in vivo models, we investigated the effect of NaHS, an exogenous donor of H2S, on the focal cerebral ischemia-reperfusion (I/R) induced brain injury. Results: Administration of NaHS significantly decreased the brain infarcted area as compared to the I/R group in a dose-dependent manner. Mechanistic studies demonstrated that NaHS-treated rats displayed significant reduction of malondialdehyde content, and strikingly increased activity of superoxide dismutases and glutathione peroxidase in the brain tissues compared with I/R group. The enhanced antioxidant capacity as well as restored mitochondrial function are NaHS-treatment correlated with decreased cellular reactive oxygen species level and compromised apoptosis in vitro or in vivo in the presence of NaHS compared with control. Further analysis revealed that the inhibition of PARP-1 cleavage and AIF translocation are involved in the neuroprotective effects of NaHS. Conclusion: Collectively, our results suggest that NaHS has potent protective effects against the brain injury induced by I/R. NaHS is possibly effective through inhibition of oxidative stress and apoptosis.

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A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.104.066944 ◽

2004 ◽

Vol 310 (2) ◽

pp. 425-436 ◽

Cited By ~ 63

Author(s):

Akinori Iwashita ◽

Nobuteru Tojo ◽

Shigeru Matsuura ◽

Syunji Yamazaki ◽

Kazunori Kamijo ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Damage ◽

In Vivo Models

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Examining the neuroprotective effects of protocatechuic acid and chrysin on in vitro and in vivo models of Parkinson disease

Free Radical Biology and Medicine ◽

10.1016/j.freeradbiomed.2015.02.030 ◽

2015 ◽

Vol 84 ◽

pp. 331-343 ◽

Cited By ~ 84

Author(s):

Zaijun Zhang ◽

Guohui Li ◽

Samuel S.W. Szeto ◽

Cheong Meng Chong ◽

Quan Quan ◽

...

Keyword(s):

Parkinson Disease ◽

Protocatechuic Acid ◽

Neuroprotective Effects ◽

In Vivo Models

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Hypothermia and Isoflurane Similarly Inhibit Glutamate Release Evoked by Chemical Anoxia in Rat Cortical Brain Slices

Anesthesiology ◽

10.1097/00000542-199609000-00020 ◽

1996 ◽

Vol 85 (3) ◽

pp. 600-607. ◽

Cited By ~ 35

Author(s):

Helge Eilers ◽

Philip E. Bickler

Keyword(s):

Minimum Alveolar Concentration ◽

Glutamate Release ◽

Brain Slices ◽

Neuronal Cell ◽

Release Rates ◽

Neuroprotective Effects ◽

In Vivo Models ◽

Chemical Anoxia

Background Accumulation of the excitatory neurotransmitter glutamate in ischemic brain tissue contributes to neuronal cell death. Volatile anesthetics at clinically relevant concentrations are neuroprotective in in vivo models of brain ischemia and reduce glutamate release in vivo and in vitro, but they appear to have weaker neuroprotective effects than hypothermia. The purpose of this study was to determine whether isoflurane reduces glutamate release in hypoxic brain slices, how large this effect is compared to that of hypothermia, and if it is diminished by hyperthermia. Methods Glutamate released from rat cortical brain slices during chemical anoxia (100 microM NaCN) was measured continuously with a fluorescence assay. The release rate was compared at three temperatures (28 degrees C, 37 degrees C, and 39 degrees C) with and without isoflurane at concentrations equipotent to 1 minimum alveolar concentration. At the same three temperatures, glutamate release rates before and after exposure to isoflurane were compared. Results Isoflurane reduced glutamate release from brain slices during chemical anoxia at 37 degrees C (19.6%, P < 0.01) and at 39 degrees C (25.4%, P < 0.01), but not at 28 degrees C. The reduction in glutamate release with hypothermia was similar to that with isoflurane. Hyperthermia (39 degrees C) caused greater glutamate release under basal and anoxic conditions than normo- and hypothermia. Isoflurane caused a slight increase in basal glutamate release rates, although this effect was smaller than the increase caused by hyperthermia. Conclusions In a brain slice model of cerebral anoxia, 1 minimum alveolar concentration isoflurane decreases glutamate release to a similar extent that hypothermia (28 degrees C) does. The increased glutamate release with hyperthermia (39 degrees C) is not prevented by isoflurane.

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Neuroprotective Effects of Ginsenosides against Cerebral Ischemia

Molecules ◽

10.3390/molecules24061102 ◽

2019 ◽

Vol 24 (6) ◽

pp. 1102 ◽

Cited By ~ 15

Author(s):

Zhekang Cheng ◽

Meng Zhang ◽

Chengli Ling ◽

Ying Zhu ◽

Hongwei Ren ◽

...

Keyword(s):

Cerebral Ischemia ◽

Ischemia Reperfusion ◽

Ischemic Injury ◽

Neurological Dysfunction ◽

Control Group ◽

Protective Effects ◽

Ginsenoside Rb1 ◽

Neuroprotective Effects

Ginseng has been used worldwide as traditional medicine for thousands of years, and ginsenosides have been proved to be the main active components for their various pharmacological activities. Based on their structures, ginsenosides can be divided into ginseng diol-type A and ginseng triol-type B with different pharmacological effects. In this study, six ginsenosides, namely ginsenoside Rb1, Rh2, Rg3, Rg5 as diol-type ginseng saponins, and Rg1 and Re as triol-type ginseng saponins, which were reported to be effective for ischemia-reperfusion (I/R) treatment, were chosen to compare their protective effects on cerebral I/R injury, and their mechanisms were studied by in vitro and in vivo experiments. It was found that all ginsenosides could reduce reactive oxygen species (ROS), inhibit apoptosis and increase mitochondrial membrane potential in cobalt chloride-induced (CoCl2-induced) PC12 cells injury model, and they could reduce cerebral infarction volume, brain neurological dysfunction of I/R rats in vivo. The results of immunohistochemistry and western blot showed that the expression of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), silencing information regulator (SIRT1) and nuclear transcription factor P65 (NF-κB) in hippocampal CA1 region of some ginsenoside groups were also reduced. In general, the effect on cerebral ischemia of Rb1 and Rg3 was significantly improved compared with the control group, and was the strongest among all the ginsenosides. The effect on SIRT1 activation of ginsenoside Rb1 and the inhibition effect of TLR4/MyD88 protein expression of ginsenoside Rb1 and Rg3 were significantly stronger than that of other groups. The results indicated that ginsenoside Rg1, Rb1, Rh2, Rg3, Rg5 and Re were effective in protecting the brain against ischemic injury, and ginsenoside Rb1 and Rg3 have the strongest therapeutic activities in all the tested ginsenosides. Their neuroprotective mechanism is associated with TLR4/MyD88 and SIRT1 activation signaling pathways, and they can reduce cerebral ischemic injury by inhibiting NF-κB transcriptional activity and the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6).

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