Changes in hippocampal synapses and learning-memory abilities in a streptozotocin-treated rat model and intervention by using fasudil hydrochloride

Hou, Yanming; Zhou, Luping; Yang, Qingda; Du, Xiaoping; Li, M.; Yuan, Mei; Zhou, Zengzi

doi:10.1016/j.neuroscience.2011.10.030

Cited by 53 publications

(35 citation statements)

References 77 publications

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“…And these deficits are paralleled by neurophysiological and structural changes in the hippocampus, the major area associated with learning and memory. Experiments in diabetic animals found that diabetes mellitus caused hippocampal neuronal apoptosis[7], reducing capacity for neurogenesis and degeneration in synaptic structures[34]. Clinical study indicated that hyperglycemia plays a critical role in hippocampus dysfunction in patients with both type 1 and type 2 diabetes mellitus[2].…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Ginsenoside Rb1 on High Glucose-Induced Neurotoxicity in Primary Cultured Rat Hippocampal Neurons

Liu

Zhang

et al. 2013

PLoS ONE

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Ginsenoside Rb1 is one of the main active principles in traditional herb ginseng and has been reported to have a wide variety of neuroprotective effects. Endoplasmic reticulum (ER) stress has been implicated in neurodegenerative diseases, so the present study aimed to observe the effects of ginsenoside Rb1 on ER stress signaling pathways in high glucose-treated hippocampal neurons. The results from MTT, TUNEL labeling and Annexin V-FITC/PI/Hoechst assays showed that incubating neurons with 50 mM high glucose for 72h decreased cell viability and increased the number of apoptotic cells whereas treating neurons with 1 μM Rb1 for 72h protected the neurons against high glucose-induced cell damage. Further molecular mechanism study demonstrated that Rb1 suppressed the activation of ER stress-associated proteins including protein kinase RNA (PKR)-like ER kinase (PERK) and C/EBP homology protein (CHOP) and downregulation of Bcl-2 induced by high glucose. Moreover, Rb1 inhibited both the elevation of intracellular reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential induced by high glucose. In addition, the high glucose-induced cell apoptosis, activation of ER stress, ROS accumulation and mitochondrial dysfunction can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA) and anti-oxidant N-acetylcysteine(NAC). In conclusion, these results suggest that Rb1 may protect neurons against high glucose-induced cell injury through inhibiting CHOP signaling pathway as well as oxidative stress and mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Ginsenoside Rb1 on High Glucose-Induced Neurotoxicity in Primary Cultured Rat Hippocampal Neurons

Liu

Zhang

et al. 2013

PLoS ONE

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“…Several studies have demonstrated the involvement of ROCKs in the cleavage of amyloid precursor protein to the toxic b-amyloid peptide (Salminen et al, 2008). In murine models of Alzheimer disease, treatment with ROCK inhibitors reduces the level of toxic b-amyloid peptide (Zhou et al, 2003), promotes elongation of dendrite arbors (Couch et al, 2010), and improves learning dysfunction (Hou et al, 2012). Furthermore, the ROCK inhibitor fasudil reduces cognitive impairment and hippocampal neurodegeneration induced by b-amyloid peptide by suppressing the inflammatory response (Song et al, 2013).…”

Section: B Clinical Evaluation and Potential Applications Of Rho-assmentioning

confidence: 99%

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Loirand¹

2015

Pharmacol Rev

167

133

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“…ROCK reportedly activates the caspase signalling cascades and promotes cellular apoptosis (Coleman et al, 2001), indicating its involvement in cell death. In a previous study, fasudil hydrochloride (fasudil), which is a potent ROCK inhibitor, was shown to improve the pathology in mouse models of brain ischaemia (Yamashita et al, 2007), Alzheimer's disease (Hou et al, 2012) and spinal muscular atrophy (SMA; Bowerman et al, 2012). These results suggest that fasudil has potential as a treatment for many neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 95%

Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis

Takata

Tanaka

Kimura

et al. 2013

British J Pharmacology

105

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Background and Purpose Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with no effective treatment. Fasudil hydrochloride (fasudil), a potent rho kinase (ROCK) inhibitor, is useful for the treatment of ischaemic diseases. In previous reports, fasudil improved pathology in mouse models of Alzheimer's disease and spinal muscular atrophy, but there is no evidence in that it can affect ALS. We therefore investigated its effects on experimental models of ALS. Experimental Approach In mice motor neuron (NSC34) cells, the neuroprotective effect of hydroxyfasudil (M3), an active metabolite of fasudil, and its mechanism were evaluated. Moreover, the effects of fasudil, 30 and 100 mg·kg−1, administered via drinking water to mutant superoxide dismutase 1 (SOD1G93A) mice were tested by measuring motor performance, survival time and histological changes, and its mechanism investigated. Key Results M3 prevented motor neuron cell death induced by SOD1G93A. Furthermore, M3 suppressed both the increase in ROCK activity and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and the reduction in phosphorylated Akt induced by SOD1G93A. These effects of M3 were attenuated by treatment with a PI3K inhibitor (LY294002). Moreover, fasudil slowed disease progression, increased survival time and reduced motor neuron loss, in SOD1G93A mice. Fasudil also attenuated the increase in ROCK activity and PTEN, and the reduction in Akt in SOD1G93A mice. Conclusions and Implications These findings indicate that fasudil may be effective at suppressing motor neuron degeneration and symptom progression in ALS. Hence, fasudil may have potential as a therapeutic agent for ALS treatment.

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Changes in hippocampal synapses and learning-memory abilities in a streptozotocin-treated rat model and intervention by using fasudil hydrochloride

Cited by 53 publications

References 77 publications

Neuroprotective Effects of Ginsenoside Rb1 on High Glucose-Induced Neurotoxicity in Primary Cultured Rat Hippocampal Neurons

Neuroprotective Effects of Ginsenoside Rb1 on High Glucose-Induced Neurotoxicity in Primary Cultured Rat Hippocampal Neurons

Rho Kinases in Health and Disease: From Basic Science to Translational Research

Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis

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