Mumefural Ameliorates Cognitive Impairment in Chronic Cerebral Hypoperfusion via Regulating the Septohippocampal Cholinergic System and Neuroinflammation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Brain Ischemia Surgery and Drug Treatment
2.3. Morris Water Maze Task
2.4. Immunohistochemical Staining
2.5. Western Blotting
2.6. Enzyme-Linked Immunosorbent Assay
2.7. Statistical Analysis
3. Results
3.1. MF Improves BCCAo-Induced Spatial Cognitive Impairment
3.2. Effects of MF on BCCAo-Induced Cholinergic System Dysfunction
3.3. Effects of MF on Myelin Degradation
3.4. Effects of MF the Expressions of Synaptic Markers
3.5. Effects of MF on the Expression of Cognition-Related Markers
3.6. MF Inhibits BCCAo-Induced Gliosis in the Hippocampus and White Matter
3.7. MF Inhibits the Activation of Neuroinflammation in BCCAo Rats
4. Discussion
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Abbreviations
CCH | Chronic cerebral hypoperfusion |
MF | Mumefural |
BCCAo | Bilateral common artery occlusion |
IL | Interleukin |
VaD | Vascular dementia |
F. mume | Fructus mume |
NLRP3 | Nucleotide binding and oligomerization domainlike receptor family pyrin domain-containing 3 |
MWM | Morris water maze |
ChAT | Choline acetyltransferase |
AChE | Acetylcholinesterase |
VAChT | Vesicular acetylcholine transporter |
Iba-1 | Ionized calcium binding adaptor molecule-1 |
GFAP | Glial fibrillary acidic protein |
MS/vDB | Medial septum/vertical limb of the diagonal band |
HDB | Horizontal limb of the diagonal band of broca |
NBM | Nucleus basalis magnocellularis |
CAMKII | Ca2+/calmodulin-dependent protein kinase II |
PSD-95 | Postsynaptic density protein-95 |
NMDAR | N-methyl-D-aspartate receptor |
BDNF | Brain-derived neurotrophic factor |
CREB | cAMP response element binding |
P2X7R | P2X7 receptor |
TLR4 | Toll-like receptor-4 |
MyD88 | Myeloid differentiation primary response 88 |
NF-κB | Nuclear factor-κB |
STAT3 | Signal transducer and activator of transcription 3 |
References
- Meyer, J.S.; Rauch, G.; Rauch, R.A.; Haque, A. Risk factors for cerebral hypoperfusion, mild cognitive impairment, and dementia. Neurobiol. Aging. 2000, 21, 161–169. [Google Scholar] [CrossRef]
- Valério Romanini, C.; Dias Fiuza Ferreira, E.; Correia Bacarin, C.; Verussa, M.H.; Weffort de Oliveira, R.M.; Milani, H. Neurohistological and behavioral changes following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats. Behav. Brain Res. 2013, 252, 214–221. [Google Scholar] [CrossRef]
- Kitagawa, K.; Yagita, Y.; Sasaki, T.; Sugiura, S.; Omura-Matsuoka, E.; Mabuchi, T.; Matsushita, K.; Hori, M. Chronic mild reduction of cerebral perfusion pressure induces ischemic tolerance in focal cerebral ischemia. Stroke 2005, 36, 2270–2274. [Google Scholar] [CrossRef]
- Farkas, E.; Luiten, P.G.; Bari, F. Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases. Brain Res. Rev. 2007, 54, 162–180. [Google Scholar] [CrossRef] [PubMed]
- Adibhatla, R.M.; Hatcher, J.F. Phospholipase A (2), reactive oxygen species, and lipid peroxidation in CNS pathologies. BMB. Rep. 2008, 41, 560–567. [Google Scholar] [CrossRef] [PubMed]
- Bang, J.; Jeon, W.K.; Lee, I.S.; Han, J.S.; Kim, B.Y. Biphasic functional regulation in hippocampus of rat with chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid artery. PLoS ONE 2013, 8, e70093. [Google Scholar] [CrossRef] [PubMed]
- Candelario-Jalil, E. Nimesulide as a promising neuroprotectant in brain ischemia: new experimental evidences. Pharmacol. Res. 2008, 57, 266–273. [Google Scholar] [CrossRef]
- Duncombe, J.; Kitamura, A.; Hase, Y.; Ihara, M.; Kalaria, R.N.; Horsburgh, K. Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia. Clin. Sci. 2017, 131, 2451–2468. [Google Scholar] [CrossRef]
- Nakao, S.; Yamamoto, T.; Kimura, S.; Mino, T.; Iwamoto, T. Brain white matter lesions and postoperative cognitive dysfunction: a review. J. Anesth. 2019, 33, 336–340. [Google Scholar] [CrossRef]
- Blake, M.G.; Boccia, M.M. Basal Forebrain Cholinergic System and Memory. Curr. Top. Behav. Neurosci. 2018, 37, 253–273. [Google Scholar]
- Cho, K.O.; Kim, S.K.; Kim, S.Y. Chronic cerebral hypoperfusion and plasticity of the posterior cerebral artery following permanent bilateral common carotid artery occlusion. Korean J. Physiol. Pharmacol. 2017, 21, 643–650. [Google Scholar] [CrossRef] [PubMed]
- Jing, Z.; Shi, C.; Zhu, L.; Xiang, Y.; Chen, P.; Xiong, Z.; Li, W.; Ruan, Y.; Huang, L. Chronic cerebral hypoperfusion induces vascular plasticity and hemodynamics but also neuronal degeneration and cognitive impairment. J. Cereb. Blood Flow Metab. 2015, 35, 1249–1259. [Google Scholar] [CrossRef] [PubMed]
- Hermawati, E.; Arfian, N.; Mustofa; Partadiredja, G. Spatial Memory Disturbance Following Transient Brain Ischemia is Associated with Vascular Remodeling in Hippocampus. Kobe. J. Med. Sci. 2018, 64, E93–E106. [Google Scholar] [PubMed]
- Lee, K.M.; Bang, J.H.; Han, J.S.; Kim, B.Y.; Lee, I.S.; Kang, H.W.; Jeon, W.K. Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat. BMC Complement Altern. Med. 2013, 13, 334. [Google Scholar] [CrossRef] [PubMed]
- Kim, M.S.; Bang, J.H.; Lee, J.; Han, J.S.; Kang, H.W.; Jeon, W.K. Fructus mume Ethanol Extract Prevents Inflammation and Normalizes the Septohippocampal Cholinergic System in a Rat Model of Chronic Cerebral Hypoperfusion. J. Med. Food 2016, 19, 196–204. [Google Scholar] [CrossRef]
- Kim, M.S.; Bang, J.H.; Lee, J.; Han, J.S.; Baik, T.G.; Jeon, W.K. Ginkgo biloba L. extract protects against chronic cerebral hypoperfusion by modulating neuroinflammation and the cholinergic system. Phytomedicine 2016, 23, 1356–1364. [Google Scholar] [CrossRef]
- Kim, M.S.; Bang, J.H.; Lee, J.; Kim, H.W.; Sung, S.H.; Han, J.S.; Jeon, W.K. Salvia miltiorrhiza extract protects white matter and the hippocampus from damage induced by chronic cerebral hypoperfusion in rats. BMC Complement Altern. Med. 2015, 15, 415. [Google Scholar] [CrossRef]
- Lee, K.M.; Bang, J.; Kim, B.Y.; Lee, I.S.; Han, J.S.; Hwang, B.Y.; Jeon, W.K. Fructus mume alleviates chronic cerebral hypoperfusion-induced white matter and hippocampal damage via inhibition of inflammation and downregulation of TLR4 and p38 MAPK signaling. BMC Complement Altern. Med. 2015, 15, 125. [Google Scholar] [CrossRef]
- Jeon, W.K.; Ma, J.; Choi, B.R.; Han, S.H.; Jin, Q.; Hwang, B.Y.; Han, J.S. Effects of Fructus mume Extract on MAPK and NF-kappaB Signaling and the Resultant Improvement in the Cognitive Deficits Induced by Chronic Cerebral Hypoperfusion. Evid. Based Complement Alternat. Med. 2012, 2012, 450838. [Google Scholar] [CrossRef]
- Park, J.C.; Ma, J.; Jeon, W.K.; Han, J.S. Fructus mume extracts alleviate cognitive impairments in 5XFAD transgenic mice. BMC Complement Altern. Med. 2016, 16, 54. [Google Scholar] [CrossRef]
- Kim, M.S.; Jeon, W.K.; Lee, K.W.; Park, Y.H.; Han, J.S. Ameliorating Effects of Ethanol Extract of Fructus mume on Scopolamine-Induced Memory Impairment in Mice. Evid. Based Complement Alternat. Med. 2015, 2015, 102734. [Google Scholar] [PubMed]
- Pharmacognosy. Committee on the Compilation of Textbooks, Parmacognosy 3rd ed.; Dongmyungsa: Seoul, Korea, 2001. [Google Scholar]
- Utsunomiya, H.; Takekoshi, S.; Gato, N.; Utatsu, H.; Motley, E.D.; Eguchi, K.; Fitzgerald, T.G.; Mifune, M.; Frank, G.D.; Eguchi, S. Fruit-juice concentrate of Asian plum inhibits growth signals of vascular smooth muscle cells induced by angiotensin II. Life Sci. 2002, 72, 659–667. [Google Scholar] [CrossRef]
- Chuda, Y.; Ono, H.; Ohnishi-Kameyama, M.; Matsumoto, K.; Nagata, T.; Kikuchi, Y. Mumefural, citric acid derivative improving blood fluidity from fruit-juice concentrate of Japanese apricot (Prunus mume Sieb. et Zucc). J. Agric. Food Chem. 1999, 47, 828–831. [Google Scholar] [CrossRef] [PubMed]
- Kubo, M.; Yamazaki, M.; Matsuda, H.; Gato, N.; Kotani, T. Effect of fruit-juice concentrate of Japanese apricot (Prunus mume SEIB. et ZUCC) on improving blood fluidity. Nat. Med. 2005, 59, 22–27. [Google Scholar]
- Ueno, Y.; Koike, M.; Shimada, Y.; Shimura, H.; Hira, K.; Tanaka, R.; Uchiyama, Y.; Hattori, N.; Urabe, T. L-carnitine enhances axonal plasticity and improves white-matter lesions after chronic hypoperfusion in rat brain. J. Cereb. Blood Flow Metab. 2015, 35, 382–391. [Google Scholar] [CrossRef] [PubMed]
- Iadecola, C. The pathobiology of vascular dementia. Neuron 2013, 80, 844–866. [Google Scholar] [CrossRef] [PubMed]
- Tsien, J.Z.; Huerta, P.T.; Tonegawa, S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell 1996, 87, 1327–1338. [Google Scholar] [CrossRef]
- Sanhueza, M.; Lisman, J. The CaMKII/NMDAR complex as a molecular memory. Mol. Brain 2013, 6, 10. [Google Scholar] [CrossRef] [PubMed]
- Tanaka, Y.; Tanaka, R.; Liu, M.; Hattori, N.; Urabe, T. Cilostazol attenuates ischemic brain injury and enhances neurogenesis in the subventricular zone of adult mice after transient focal cerebral ischemia. Neuroscience 2010, 171, 1367–1376. [Google Scholar] [CrossRef]
- Yi, J.H.; Hye Jin, P.; Beak, S.J.; Lee, S.; Jung, J.W.; Kim, B.C.; Ryu, J.H.; Kim, D.H. Danggui-Jakyak-San enhances hippocampal long-term potentiation through the ERK/CREB/BDNF cascade. J. Ethnopharmacol. 2015, 175, 481–489. [Google Scholar]
- Saggu, R.; Schumacher, T.; Gerich, F.; Rakers, C.; Tai, K.; Delekate, A.; Petzold, G.C. Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia. Acta. Neuropathol. Commun. 2016, 4, 76. [Google Scholar] [CrossRef] [PubMed]
- Hase, Y.; Craggs, L.; Hase, M.; Stevenson, W.; Slade, J.; Lopez, D.; Mehta, R.; Chen, A.; Liang, D.; Oakley, A.; et al. Effects of environmental enrichment on white matter glial responses in a mouse model of chronic cerebral hypoperfusion. J. Neuroinflamm. 2017, 14, 81. [Google Scholar] [CrossRef] [PubMed]
- Shang, J.; Yamashita, T.; Zhai, Y.; Nakano, Y.; Morihara, R.; Li, X.; Huang, Y.; Shi, X.; Sato, K.; Takemoto, M.; et al. Acceleration of NLRP3 inflammasome by chronic cerebral hypoperfusion in Alzheimer’s disease model mouse. Neurosci. Res. 2019, 143, 61–70. [Google Scholar] [CrossRef] [PubMed]
- Liu, D.; Zeng, X.; Li, X.; Mehta, J.L.; Wang, X. Role of NLRP3 inflammasome in the pathogenesis of cardiovascular diseases. Basic Res. Cardiol. 2017, 113, 5. [Google Scholar] [CrossRef] [PubMed]
- Gao, L.; Dong, Q.; Song, Z.; Shen, F.; Shi, J.; Li, Y. NLRP3 inflammasome: a promising target in ischemic stroke. Inflamm. Res. 2017, 66, 17–24. [Google Scholar] [CrossRef] [PubMed]
- Song, S.Y.; Jung, Y.Y.; Hwang, C.J.; Lee, H.P.; Sok, C.H.; Kim, J.H.; Lee, S.M.; Seo, H.O.; Hyun, B.K.; Choi, D.Y.; et al. Inhibitory effect of ent-Sauchinone on amyloidogenesis via inhibition of STAT3-mediated NF-kappaB activation in cultured astrocytes and microglial BV-2 cells. J. Neroinflamm. 2014, 11, 118. [Google Scholar] [CrossRef] [Green Version]
- Kuang, X.; Wang, L.F.; Yu, L.; Li, Y.J.; Wang, Y.N.; He, Q.; Chen, C.; Du, J.R. Ligustilide ameliorates neuroinflammation and brain injury in focal cerebral ischemia/reperfusion rats: involvement of inhibition of TLR4/peroxiredoxin 6 signaling. Free Radic. Biol. Med. 2014, 71, 165–175. [Google Scholar] [CrossRef]
- Lee, S.; Chang, W.; Lu, K.; Lo, D.; Wu, M. Antioxidant capacity and Hepatoprotective effect on ethanol-injured liver cell of lemon juice concentrates and its comparison with commercial Japanese apricot juice concentrates. Res. J. Pharmaceutical. Sci. 2013, 2, 7–14. [Google Scholar]
- Nishimura, M.; Kume, H.; Kadowaki, A.; Gato, N.; Nishihira, J. Effects and safety of daily ingestion of plum extract on blood pressure: randomized, double-blinded, placebo-controlled parallel group comparison study. Funct. Foods Health Disease 2017, 7, 873–888. [Google Scholar]
- Gato, N.; Ono, H.; Kikuchi, Y.; Chuda, Y. Mumefural-related compounds in fruit-juice concentrate of Japanese apricot and their ameliorating effect on blood fluidity through capillaries. Hemorheol. Relat. Res. 2000, 3, 81–88. [Google Scholar]
- Vorhees, C.V.; Williams, M.T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 2006, 1, 848–858. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- D’Hooge, R.; De Deyn, P.P. Applications of the Morris water maze in the study of learning and memory. Brain Res. Brain Res. Rev. 2001, 36, 60–90. [Google Scholar] [CrossRef]
- Tanaka, K.; Ogawa, N.; Asanuma, M.; Kondo, Y.; Nomura, M. Relationship between cholinergic dysfunction and discrimination learning disabilities in Wistar rats following chronic cerebral hypoperfusion. Brain Res. 1996, 729, 55–65. [Google Scholar] [CrossRef]
- Jia, J.P.; Jia, J.M.; Zhou, W.D.; Xu, M.; Chu, C.B.; Yan, X.; Sun, Y.X. Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer’s disease and vascular dementia. Chin. Med. J. 2004, 117, 1161–1164. [Google Scholar]
- Okada, K.; Nishizawa, K.; Kobayashi, T.; Sakata, S.; Kobayashi, K. Distinct roles of basal forebrain cholinergic neurons in spatial and object recognition memory. Sci. Rep. 2015, 5, 13158. [Google Scholar] [CrossRef] [Green Version]
- Neumann, J.T.; Cohan, C.H.; Dave, K.R.; Wright, C.B.; Perez-Pinzon, M.A. Global cerebral ischemia: synaptic and cognitive dysfunction. Curr. Drug Targets 2013, 14, 20–35. [Google Scholar] [CrossRef] [PubMed]
- Sinclair, L.I.; Tayler, H.M.; Love, S. Synaptic protein levels altered in vascular dementia. Neuropathol. Appl. Neurobiol. 2015, 41, 533–543. [Google Scholar] [CrossRef] [Green Version]
- Lisman, J.; Yasuda, R.; Raghavachari, S. Mechanisms of CaMKII action in long-term potentiation. Nat. Rev. Neurosci. 2012, 13, 169–182. [Google Scholar] [CrossRef] [Green Version]
- Alberini, C.M. Transcription factors in long-term memory and synaptic plasticity. Physiol. Rev. 2009, 89, 121–145. [Google Scholar] [CrossRef]
- Kandel, E.R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain 2012, 5, 14. [Google Scholar] [CrossRef] [Green Version]
- Wang, J.; Zhang, H.Y.; Tang, X.C. Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion. J. Neurosci. Res. 2010, 88, 807–815. [Google Scholar] [CrossRef] [PubMed]
- Bours, M.J.; Dagnelie, P.C.; Giuliani, A.L.; Wesselius, A.; Di Virgilio, F. P2 receptors and extracellular ATP: a novel homeostatic pathway in inflammation. Front Biosci. 2011, 3, 1443–1456. [Google Scholar]
- Thakkar, R.; Wang, R.; Sareddy, G.; Wang, J.; Thiruvaiyaru, D.; Vadlamudi, R.; Zhang, Q.; Brann, D. NLRP3 inflammasome activation in the brain after global cerebral ischemia and regulation by 17β-estradiol. Oxid. Med. Cell Longev. 2016, 2016, 8309031. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhan, X.; Cox, C.; Ander, B.P.; Liu, D.; Stamova, B.; Jin, L.W.; Jickling, G.C.; Sharp, F.R. Inflammation combined with ischemia produces myelin injury and plaque-like aggregates of myelin, amyloid-beta and AbetaPP in adult rat brain. J. Alzheimers Dis. 2015, 46, 507–523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Choi, B.R.; Kim, D.H.; Back, D.B.; Kang, C.H.; Moon, W.J.; Han, J.S.; Choi, D.H.; Kwon, K.J.; Shin, C.Y.; Kim, B.R.; et al. Characterization of white matter injury in a rat model of chronic cerebral hypoperfusion. Stroke 2016, 47, 542–547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Goldstein, A.; Mesfin, F.B. Neuroanatomy, Corpus Callosum; StatPearls Publishing: Treasure Island, FL, USA, 2019. [Google Scholar]
Antibodies | Companies | Dilution | |
---|---|---|---|
Cholinergic System Dysfunction | ChAT | Millipore | 1:500 |
AChE | Abcam | 1:1000 | |
VAChT | Millipore | 1:1000 | |
Myelin Degradation | MBP | Abcam | 1:2000 |
Synapse Plasticity | PSD-95 | Almone Labs | 1:1000 |
Synaptophysin-1 | Almone Labs | 1:1000 | |
p-CaMKII | Cell signaling | 1:1000 | |
CAMKII | Cell signaling | 1:1000 | |
NMDAR2A | Abcam | 1:1000 | |
NMDAR2B | Abcam | 1:1000 | |
Cognitive Function | BDNF | Abcam | 1:1000 |
p-CREB | Cell signaling | 1:1000 | |
CREB | Cell signaling | 1:1000 | |
Gliosis | Iba-1 | Wako | 1:1000 |
GFAP | Sigma Aldrich | 1:2000 | |
Inflammation | P2X7R | Almone Labs | 1:2000 |
TLR4 | Santa Cruz | 1:1000 | |
MyD88 | Santa Cruz | 1:1000 | |
NLRP3 | Abcam | 1:1000 | |
Caspase1 | Abcam | 1:1000 | |
IL-1β | Abcam | 1:1000 | |
IL-18 | Millipore | 1:1000 | |
p-STAT3 (Tyr705) | Cell signaling | 1:1000 | |
p-STAT3 (Ser727) | Cell signaling | 1:1000 | |
STAT3 | Cell signaling | 1:1000 | |
p-65 | Santa Cruz | 1:1000 | |
p-50 | Santa Cruz | 1:1000 | |
Internal Controls | Lamin B1 | Sigma Aldrich | 1:500 |
β-actin | Sigma Aldrich | 1:2000 |
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Bang, J.; Kim, M.-S.; Jeon, W.K. Mumefural Ameliorates Cognitive Impairment in Chronic Cerebral Hypoperfusion via Regulating the Septohippocampal Cholinergic System and Neuroinflammation. Nutrients 2019, 11, 2755. https://doi.org/10.3390/nu11112755
Bang J, Kim M-S, Jeon WK. Mumefural Ameliorates Cognitive Impairment in Chronic Cerebral Hypoperfusion via Regulating the Septohippocampal Cholinergic System and Neuroinflammation. Nutrients. 2019; 11(11):2755. https://doi.org/10.3390/nu11112755
Chicago/Turabian StyleBang, Jihye, Min-Soo Kim, and Won Kyung Jeon. 2019. "Mumefural Ameliorates Cognitive Impairment in Chronic Cerebral Hypoperfusion via Regulating the Septohippocampal Cholinergic System and Neuroinflammation" Nutrients 11, no. 11: 2755. https://doi.org/10.3390/nu11112755