Isoquercetin Ameliorates Cerebral Impairment in Focal Ischemia Through Anti-Oxidative, Anti-Inflammatory, and Anti-Apoptotic Effects in Primary Culture of Rat Hippocampal Neurons and Hippocampal CA1 Region of Rats

Rhodioloside, the main effective constituent of Rhodiola rosea, demonstrates antiaging and antioxidative stress functions and inhibits calcium overloading in cells. These functions imply that rhodioloside may exert protective effects on hippocampal neurons after total cerebral ischemia/reperfusion injury. In this study, male Wistar rat models of total cerebral ischemia were constructed and randomly divided into four groups: sham-operation, ischemia/reperfusion, low-dosage, and high-dosage groups. The result showed that rhodioloside treatment reduced the apoptosis rates of hippocampal neurons and the histological grades of cone cells in the hippocampal CA1 region, but neuronal density was significantly increased. Besides, the protein expressions of Bcl-2/Bax and p53 were measured and found Bcl-2/Bax was increased and p53 protein level was reduced. Therefore, rhodioloside might have protective effects on rats with ischemia/reperfusion brain injury.

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Melanin Concentrating Hormone- and sleep-dependent synaptic downscaling is impaired in Alzheimer's Disease

10.1101/2021.05.21.445007 ◽

2021 ◽

Author(s):

Sara Calafate ◽

Gokhan Ozturan ◽

Nicky Thrupp ◽

Jeroen Vanderlinden ◽

Wei-Ting Chen ◽

...

Keyword(s):

Neuronal Activity ◽

Hippocampal Neurons ◽

Homeostatic Plasticity ◽

Neuron Activity ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Melanin Concentrating Hormone ◽

Encoding Gene ◽

Homeostatic Response

In Alzheimers disease (AD), pathophysiological changes in the hippocampus cause deficits in episodic memory formation, leading to cognitive impairment. Neuronal hyperactivity is observed early in AD. Here, we find that homeostatic mechanisms transiently counteract increased neuronal activity in the hippocampal CA1 region of the AppNL-G-F humanized knock-in mouse model for AD, but ultimately fail to maintain neuronal activity at set-point. Spatial transcriptomic analysis in CA1 during the homeostatic response identifies the Melanin-Concentrating Hormone (MCH)-encoding gene. MCH is expressed in sleep-active lateral hypothalamic neurons that project to CA1 and modulate memory. We show that MCH regulates synaptic plasticity genes and synaptic downscaling in hippocampal neurons. Furthermore, MCH-neuron activity is impaired in AppNL-G-F mice, disrupting sleep-dependent homeostatic plasticity and stability of neuronal activity in CA1. Finally, we find perturbed MCH-axon morphology in CA1 early in AppNL-G-F mice and in AD patients. Our work identifies dysregulation of the MCH-system as a key player in aberrant neuronal activity in the early stages of AD.

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Data-driven integration of hippocampal CA1 synapse physiology in silico

10.1101/716480 ◽

2019 ◽

Author(s):

András Ecker ◽

Armando Romani ◽

Sára Sáray ◽

Szabolcs Káli ◽

Michele Migliore ◽

...

Keyword(s):

In Silico ◽

Hippocampal Neurons ◽

Data Driven ◽

Extensive Literature ◽

Anatomy And Physiology ◽

Integrative Framework ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Data Driven Approach

AbstractThe anatomy and physiology of synaptic connections in rodent hippocampal CA1 have been exhaustively characterized in recent decades. Yet, the resulting knowledge remains disparate and difficult to reconcile. Here, we present a data-driven approach to integrate the current state-of-the-art knowledge on the synaptic anatomy and physiology of rodent hippocampal CA1, including axo-dendritic innervation patterns, number of synapses per connection, quantal conductances, neurotransmitter release probability, and short-term plasticity into a single coherent resource. First, we undertook an extensive literature review of paired-recordings of hippocampal neurons and compiled experimental data on their synaptic anatomy and physiology. The data collected in this manner is sparse and inhomogeneous due to the diversity of experimental techniques used by different labs, which necessitates the need for an integrative framework to unify these data. To this end, we extended a previously developed workflow for the neocortex to constrain a unifying in silico reconstruction of the synaptic physiology of CA1 connections. Our work identifies gaps in the existing knowledge and provides a complementary resource towards a more complete quantification of synaptic anatomy and physiology in the rodent hippocampal CA1 region.

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G-Protein-Coupled Estrogen Receptor Activation Upregulates Interleukin-1 Receptor Antagonist in the Hippocampus after Global Cerebral Ischemia: Implications for Neuronal Self Defense

10.21203/rs.2.18901/v2 ◽

2020 ◽

Author(s):

NING BAI ◽

QUANGUANG ZHANG ◽

WENLI ZHANG ◽

BIN LIU ◽

FANG YANG ◽

...

Keyword(s):

Estrogen Receptor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Global Cerebral Ischemia ◽

Immunofluorescent Staining ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Anti Inflammatory ◽

G Protein Coupled

Abstract Background: G-protein-Coupled Estrogen Receptor (GPER/GPR30) is a novel membrane-associated estrogen receptor that can induce rapid kinase signaling in various cells. Activation of GPER can prevent hippocampal neuronal cell death following transient global cerebral ischemia (GCI), although the mechanisms remain unclear. In the current study, we sought to address whether GPER activation exerts potent anti-inflammatory effects in the rat hippocampus after GCI as a potential mechanism to limit neuronal cell death. Methods: GCI was induced by four-vessel occlusion in ovariectomized-female SD rats. Specific agonist G1 or antagonist G36 of GPER was administrated using minipump and antisense oligonucleotide (AS) of interleukin-1β receptor antagonist (IL1RA) was administrated using brain infusion kit. Protein expression of IL1RA, NFkB-P65, phosphorylation of CREB (p-CREB), Bcl2, Cleaved-caspase 3 and microglial markers Iba1, CD11b, as well as inflammasome components NLRP3, ASC, Cleaved-caspase 1, and Cle-IL1β in the hippocampal CA1 region were investigated by Immunofluorescent staining and Western blot analysis. The Duo-Link II in situ proximity ligation assay (PLA) was performed to detect the interaction between NLRP3 and ASC. Immunofluorescent staining for NeuN and TUNEL analysis were used to analyze neuronal survival and apoptosis, respectively. We performed Barnes maze and Novel object tests to compare the cognitive function of the rats. Results: The results showed that G1 attenuated GCI-induced elevation of Iba1 and CD11b in the hippocampal CA1 region at 14d reperfusion, and this effect was blocked by G36. G1 treatment also markedly decreased expression of the NLRP3-ASC-Caspase 1 inflammasome and IL1β activation, as well as downstream NFkB signaling, the effects reversed by G36 administration. Intriguingly, G1 caused a robust elevation in neurons of a well-known endogenous anti-inflammatory factor IL1RA, which was reversed by G36 treatment. G1 also enhanced p-CREB level in the hippocampus, a transcription factor known to enhance expression of IL1RA. Finally, in vivo IL1RA-AS abolished the anti-inflammatory, neuroprotective and anti-apoptotic effects of G1 after GCI, and reversed the cognitive-enhancing effects of G1 at 14d after GCI. Conclusions: Taken together, the current results suggest that GPER preserves cognitive function following GCI in part by exerting anti-inflammatory effects and enhancing the defense mechanism of neurons by upregulating IL1RA.

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Somatostatin modulates high-voltage-activated Ca2+ channels in freshly dissociated rat hippocampal neurons

Journal of Neurophysiology ◽

10.1152/jn.1995.74.3.1028 ◽

1995 ◽

Vol 74 (3) ◽

pp. 1028-1036 ◽

Cited By ~ 54

Author(s):

H. Ishibashi ◽

N. Akaike

Keyword(s):

High Voltage ◽

Hippocampal Neurons ◽

Pyramidal Neurons ◽

Low Voltage ◽

Inhibitory Effect ◽

Dependent Manner ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Ca2 Channels

1. The effects of somatostatin (SS) on the low-voltage-activated and high-voltage-activated (HVA) Ca2+ channels in pyramidal neurons acutely dissociated from the hippocampal CA1 region of 2- to 3-wk-old rats were investigated in a nystatin perforated-patch recording configuration under voltage-clamp conditions. 2. SS had no effect on the low-voltage-activated Ca2+ channel but did inhibit the HVA Ca2+ channel in a concentration-, time-, and voltage-dependent manner. 3. SS showed the activation phase of Ba2+ current (IBa) passing through HVA Ca2+ channels, and the maximum inhibition was 28% of the total current amplitude measured 10 ms after the current activation. The inhibitory effect was eliminated by applying larger depolarizing prepulses. Pretreatment with pertussis toxin (PTX) completely blocked the effect of SS on HVA IBa, suggesting the contribution of PTX-sensitive Gi/Go proteins to the SS-induced inhibition. 4. The applications of forskolin, 8-Br-cAMP, dibutyryl-guanosine 3'5'-cyclic monophosphate, staurosporine, and 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine did not affect either the control HVA IBa or the SS-induced inhibition of HVA IBa. 5. Pretreatment with protein kinase C (PKC) activators had no significant effect on HVA IBa but did remove the inhibition of HVA IBa by SS. 6. Omega-Conotoxin-GVIA, omega-agatoxin-IVA, nicardipine, and omega-conotoxin-MVIIC blocked HVA IBa by 27, 13, 38, and 9% of the total HVA current, respectively, which suggested the existence of N-, P-, L-, and Q-type HVA Ca2+ channels in the hippocampal CA1 pyramidal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

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G-Protein-Coupled Estrogen Receptor Activation Upregulates Interleukin-1 Receptor Antagonist in the Hippocampus after Global Cerebral Ischemia: Implications for Neuronal Self Defense

10.21203/rs.2.18901/v1 ◽

2019 ◽

Author(s):

NING BAI ◽

QUANGUANG ZHANG ◽

WENLI ZHANG ◽

BIN LIU ◽

FANG YANG ◽

...

Keyword(s):

Estrogen Receptor ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Global Cerebral Ischemia ◽

Immunofluorescent Staining ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Anti Inflammatory ◽

G Protein Coupled

Abstract Background: G-protein-Coupled Estrogen Receptor (GPER/GPR30) is a novel membrane-associated estrogen receptor that can induce rapid kinase signaling in various cells. Activation of GPER can prevent hippocampal neuronal cell death following transient global cerebral ischemia (GCI), although the mechanisms remain unclear. In the current study, we sought to address whether GPER activation exerts potent anti-inflammatory effects in the rat hippocampus after GCI as a potential mechanism to limit neuronal cell death. Methods: GCI was induced by four-vessel occlusion in ovariectomized-female SD rats. Specific agonist G1 or antagonist G36 of GPER was administrated using minipump and antisense oligonucleotide (AS) of interleukin-1β receptor antagonist (IL1RA) was administrated using brain infusion kit. Protein expression of IL1RA, NFkB-P65, phosphorylation of CREB (p-CREB), Bcl2, Cleaved-caspase 3 and microglial markers Iba1, CD11b, as well as inflammasome components NLRP3, ASC, Cleaved-caspase 1, and Cle-IL1β in the hippocampal CA1 region were investigated by Immunofluorescent staining and Western blot analysis. The Duo-Link II in situ proximity ligation assay (PLA) was performed to detect the interaction between NLRP3 and ASC. Immunofluorescent staining for NeuN and TUNEL analysis were used to analyze neuronal survival and apoptosis, respectively. We performed Barnes maze and Novel object tests to compare the cognitive function of the rats. Results: The results showed that G1 attenuated GCI-induced elevation of Iba1 and CD11b in the hippocampal CA1 region at 14d reperfusion, and this effect was blocked by G36. G1 treatment also markedly decreased expression of the NLRP3-ASC-Caspase 1 inflammasome and IL1β activation, as well as downstream NFkB signaling, the effects reversed by G36 administration. Intriguingly, G1 caused a robust elevation in neurons of a well-known endogenous anti-inflammatory factor IL1RA, which was reversed by G36 treatment. G1 also enhanced p-CREB level in the hippocampus, a transcription factor known to enhance expression of IL1RA. Finally, in vivo IL1RA-AS abolished the anti-inflammatory, neuroprotective and anti-apoptotic effects of G1 after GCI, and reversed the cognitive-enhancing effects of G1 at 14d after GCI. Conclusions: Taken together, the current results suggest that GPER preserves cognitive function following GCI in part by exerting anti-inflammatory effects and enhancing the defense mechanism of neurons by upregulating IL1RA.

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Maintenance of anti-inflammatory cytokines and reduction of glial activation in the ischemic hippocampal CA1 region preconditioned with lipopolysaccharide

Journal of the Neurological Sciences ◽

10.1016/j.jns.2010.06.004 ◽

2010 ◽

Vol 296 (1-2) ◽

pp. 69-78 ◽

Cited By ~ 30

Author(s):

Jia Tian Yu ◽

Choong Hyun Lee ◽

Ki-Yeon Yoo ◽

Jung Hoon Choi ◽

Hua Li ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Glial Activation ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Anti Inflammatory

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Neuroprotective Effects of Purpurin Against Ischemic Damage via Anti-inflammatory and MAPK Pathway

10.21203/rs.3.rs-788893/v1 ◽

2021 ◽

Author(s):

Woosuk Kim ◽

Hyun Jung Kwon ◽

Hyo Young Jung ◽

Kyu Ri Hahn ◽

Yeo Sung Yoon ◽

...

Keyword(s):

Oxidative Stress ◽

Mapk Pathway ◽

Ischemic Damage ◽

Neuroprotective Effects ◽

Ht22 Cells ◽

Protein Levels ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Hippocampal Ca1 ◽

Anti Inflammatory

Abstract Purpurin has various effects, including anti-inflammatory effects, and can efficiently cross the blood-brain barrier. In the present study, we investigated the effects of purpurin on oxidative stress in HT22 cells and ischemic damage in the hippocampal CA1 region of gerbils. Oxidative stress induced by H2O2 was significantly ameliorated by treatment with purpurin, based on changes in cell death, DNA fragmentation, formation of reactive oxygen species, and apoptosis (Bcl-2)/antiapoptosis (Bax)-related protein levels. In addition, treatment with purpurin significantly reduced the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK), and p38 signaling in HT22 cells. Transient forebrain ischemia in gerbils led to a significant increase in locomotor activity 1 day after ischemia and significant decrease in number of surviving cells in the CA1 region 4 days after ischemia. Administration of purpurin reduced the travel distance 1 day after ischemia and increased the number of NeuN-immunoreactive neurons in the hippocampal CA1 region of the dentate gyrus 4 days after ischemia. Purpurin treatment significantly decreased microglial activation in the hippocampal CA1 region 4 days after ischemia and ameliorated the ischemia-induced increases in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α 6 h after ischemia. In addition, purpurin significantly alleviated the ischemia-induced phosphorylation of JNK, ERK, and p38 in the hippocampus 1 day after ischemia. These results suggest that purpurin has neuroprotective potential to reduce inflammatory processes and the phosphorylation of JNK, ERK, and p38 in the hippocampus.

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