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Neuroprotective Effect of Genistein: Studies in Rat Models of Parkinson’s and Alzheimer’s Disease
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are neurodegenerative disorders that mainly affect the elderly population. It is believed that oxidative stress is involved in development of both these diseases and that estrogen deficiency is a risk factor for development of AD. Genistein is a plant-derived compound that is similar in structure to estrogen and has anti-oxidative properties. The general objective of the present research was to evaluate the effects of genistein on neurodegeneration in rat models of PD and AD.

Using a rat model of PD, we found that a single intraperitoneal dose of genistein 1 h before intrastriatal injection of 6-hydroxydopamine (6-OHDA) attenuated apomorphine-induced rotational behavior and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity.

To produce an animal model of AD, we injected Aβ1–40 into the hippocampus of rats. Using groups of these Aβ1–40-lesioned animals, the involvement of estrogen receptors (ERs) was evaluated by intracerebroventricular injection of the estrogen receptor antagonist fulvestrant, and the role of oxidative stress was studied by measuring levels of malondialdehyde (MDA), nitrite, and superoxide dismutase (SOD) activity. The results showed that intrahippocampal injection of Aβ1–40 caused the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in a radial arm maze (RAM task), elevated levels of MDA and nitrite, and a signiHcant reduction in SOD activity in the brain tissue. Furthermore, hippocampus in theses rats exhibited Aβ1–40 immunoreactive aggregates close to the lateral blade of the dentate gyrus (DGlb), extensive neuronal degeneration in the DGlb, high intracellular iNOS+ and nNOS+ immunoreactivity, and extensive astrogliosis.

Genistein pretreatment ameliorated the Aβ-induced impairment of short-term spatial memory, and this effect occurred via an estrogenic pathway and through attenuation of oxidative stress. Genistein also ameliorated the degeneration of neurons, inhibited the formation of Aβ1–40-positive aggregates, and alleviated Aβ1–40-induced astrogliosis in the hippocampus.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1288
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-77173ISBN: 978-91-7519-984-9 (print)OAI: oai:DiVA.org:liu-77173DiVA: diva2:525329
Public defence
2012-06-04, Berzeliussalen, Hälsouniversitetet, Campus Valla, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2016-02-29Bibliographically approved
List of papers
1. Neuroprotective Effect of Genistein in 6-Hydroxydopamine Hemi-parkinsonian Rat Model
Open this publication in new window or tab >>Neuroprotective Effect of Genistein in 6-Hydroxydopamine Hemi-parkinsonian Rat Model
2008 (English)In: Phytotherapy Research, ISSN 0951-418X, E-ISSN 1099-1573, Vol. 23, no 1, 132-135 p.Article in journal (Refereed) Published
Abstract [en]

A large body of experimental evidence supports a role for oxidative stress as a mediator of nerve cell death in Parkinson-s disease (PD). Phytoestrogens such as genistein have been reported to prevent neuronal degeneration caused by increased oxidative burden, therefore, this study examined whether genistein administration at a high dose would attenuate behavioral and structural abnormalities in an experimental model of PD in rat. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA, 12.5 μg/5 μL of saline-ascorbate)- lesioned rats were intraperitoneally pretreated with a single and high dose of genistein (10 mg/kg) 1 h before surgery. Apomorphine-induced rotations and the number of Nissl-stained neurons in the substantia nigra pars compacta (SNC) were counted after 2 weeks. Genistein administration could attenuate the rotational behavior in lesioned rats and protect the neurons of SNC against 6-OHDA toxicity. Genistein administration has a protective effect against 6-OHDA toxicity. 

Keyword
genistein • Parkinson's disease • 6-hydroxydopamine • rotation • rat
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-44303 (URN)10.1002/ptr.2564 (DOI)18693302 (PubMedID)76209 (Local ID)76209 (Archive number)76209 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13
2. Genistein ameliorates learning and memory deficits in amyloid beta((1-40)) rat model of Alzheimers disease
Open this publication in new window or tab >>Genistein ameliorates learning and memory deficits in amyloid beta((1-40)) rat model of Alzheimers disease
2011 (English)In: Neurobiology of Learning and Memory, ISSN 1074-7427, E-ISSN 1095-9564, Vol. 95, no 3, 270-276 p.Article in journal (Refereed) Published
Abstract [en]

Alzheimers disease (AD) is a debilitating neurodegenerative disorder characterized by increased beta-amyloid (A beta) deposition and neuronal dysfunction leading to impaired learning and recall. Ageing, heredity, and induced oxidative stress are among proposed risk factors. The increased frequency of the disease in women also suggests a role for estrogen in development of AD. In the present study, effects of the phytoestrogen genistein (10 mg/kg) on learning and memory impairments was assessed in intrahippocampal A beta((1-40))-injected rats. The estrogen receptor antagonist fulvestrant was injected intracerebroventricularly in a group of A beta-lesioned rats. The A beta-injected animals exhibited the following: lower spontaneous alternation score in Y-maze tasks, impaired retention and recall capability in the passive avoidance test, and fewer correct choices and more errors in the RAM task. Genistein, but not genistein and fulvestrant, significantly improved most of these parameters. Measurements of oxidative stress markers in hippocampal tissue of A beta-injected rats showed an elevation of malondialdehyde (MDA) and nitrite content, and a reduction of superoxide dismutase (SOD) activity. Genistein significantly attenuated the increased MDA content but did not affect the nitrite content or SOD activity. These results indicate that genistein pretreatment ameliorates A beta-induced impairment of short-term spatial memory in rats through an estrogenic pathway and by inducing attenuation of oxidative stress.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam, 2011
Keyword
Alzheimers disease, Beta-amyloid, Genistein, Learning and memory
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67550 (URN)10.1016/j.nlm.2010.12.001 (DOI)000288774300006 ()
Note
Original Publication: Maryam Bagheri, Mohammad-Taghi Joghataei, Simin Mohseni and Mehrdad Roghani, Genistein ameliorates learning and memory deficits in amyloid beta((1-40)) rat model of Alzheimers disease, 2011, NEUROBIOLOGY OF LEARNING AND MEMORY, (95), 3, 270-276. http://dx.doi.org/10.1016/j.nlm.2010.12.001 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/Available from: 2011-04-18 Created: 2011-04-18 Last updated: 2017-12-11Bibliographically approved
3. Genistein inhibits aggregation of exogenous amyloid-beta(1-40) and alleviates astrogliosis in the hippocampus of rats
Open this publication in new window or tab >>Genistein inhibits aggregation of exogenous amyloid-beta(1-40) and alleviates astrogliosis in the hippocampus of rats
2012 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1429, 145-154 p.Article in journal (Refereed) Published
Abstract [en]

We addressed the question of whether injection of Amyloid beta (Aβ)(1-40) in the rat brain is associated with pathology in the hippocampus, and if genistein has any protective effect against the neuronal damage caused by Aβ(1-40). Genistein is a plant-derived compound with a structure similar to that of the female sex hormone estrogen and it was recently shown that pretreatment with a single dose of genistein ameliorated learning and memory deficits in an (Aβ)(1-40) rat model of Alzheimer's disease. Here, we report that injection of the amyloid peptide into the hippocampus of rats led to formation of Aβ(1-40) positive aggregates close to the lateral blade of the dentate gyrus (DGlb). We also observed the following in the hippocampus: extensive cell death in the DGlb (P<0.0001), CA1 (P=0.03), and CA3 (P=0.002); an increased number of iNOS-expressing cells (P=0.01) and gliosis. Genistein given to rats by gavage 1h before injection of Aβ(1-40) inhibited the formation of Aβ(1-40) positive aggregates in the brain tissue and led to increased number of nNOS(+) (P=0.0001) cells in the hippocampus compared to sham-operated genistein-treated controls. Treatment with genistein also alleviated the extensive astrogliosis that occurred in Aβ(1-40)-injected hippocampus to a level similar to that observed in sham-operated rats. We conclude that the neurons in the DGlb are most sensitive to Aβ(1-40), and a single dose of genistein can ameliorate Aβ(1-40) induced pathology.

Place, publisher, year, edition, pages
Elsevier, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-72775 (URN)10.1016/j.brainres.2011.10.020 (DOI)000300268200016 ()22079317 (PubMedID)
Note
funding agencies|Cellular and Molecular Research Center at Tehran University of Medical Sciences (Tehran)||Linkoping University (Linkoping, Sweden)||County Council of Ostergotland||Available from: 2011-12-07 Created: 2011-12-07 Last updated: 2017-12-08Bibliographically approved
4. Genistein inhibits Aβ1-40-induced astrogliosis: A three-dimensional confocal morphometric analysis
Open this publication in new window or tab >>Genistein inhibits Aβ1-40-induced astrogliosis: A three-dimensional confocal morphometric analysis
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Astrocytes are highly involved in regulation and homeostasis of the extracellular environment in the healthy brain. In pathological conditions, these cells play a major role in the inflammatory response seen in CNS tissues, which is called reactive astrogliosis and includes hypertrophy, proliferation, and remodeling. Here, we performed 3D confocal microscopy to evaluate the morphology of reactive glial fibrillary acidic protein (GFAP-positive) astrocytes in an animal model of Alzheimer’s disease, and we also assessed the effect of the antiinflammatory agent genistein on amyloid-beta-induced astrogliosis. In 50 astrocytes/animal, we measured the area and volume of the nucleus, cell body, astrocyte (soma and branches) and territory (tissue covered by each astrocyte), and total length of the branches. Moreover, we quantified the intensity of GFAP immunoreactivity in the hippocampus. Injecting amyloid beta (Aβ)1–40 into the brain caused astrogliosis, observed as significantly higher GFAP intensity in the hippocampus, and also led to significant enlargement of astrocytes in this area, indicated by increased values for all the above-mentioned parameters. In Aβ1–40-injected rats pretreated with genistein, GFAP intensity was decreased to the level seen in the shamoperated group, and Aβ1–40-induced enlargement of astrocytes was significantly inhibited. Interestingly, genistein also ameliorated the astrogliosis that was initiated by mechanical injury caused by insertion of the injection needle into the brain tissue. This  was indicated by the observation that the mean cell body volume and area of astrocytes were significantly smaller in the genistein-treated rats, even in comparison with the sham-operated animals.

Keyword
Alzheimer’s disease; astrocytes; amyloid beta; genistein; gliosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77172 (URN)
Available from: 2012-05-07 Created: 2012-05-07 Last updated: 2016-02-29Bibliographically approved

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