The topic of this paper is estrogen’s neuroprotective mechanism in reference to neuronal injury and repair and the actual method of neuroprotection estrogens utilize. Estrogens play a monumental role in protection from brain injury and neurodegenerative disease (Lebesgue, 2009). Research questions dealt with estrogen’s specific mechanism for neuroprotection and whether or not estrogen’s neuroprotection changed over a life time. Research on estrogen’s neuroprotective mechanisms is emerging and growing every year. This paper will discuss two papers with varying results on how estrogen protects neurons and other nervous tissue.
Methods of the literature to be reviewed are animal testing and statistics. The animals were tested for a base line, placed under various forms of neuronal injury in the presence of estrogens, and tested again. The animals who had a higher concentration of estrogen recovered and performed better than the animals with less estrogens. Estrogen’s neuroprotection is not yet well understood, but science is recognizing its immense aid in protecting neurons from extensive damage. Estrogen is a human sex hormone, abundant in females, notably responsible for developing female reproductive organs.
Types of estrogens include: estrone, estradiol, estriol, estetrol. Neuroprotection is, according to F. J. Vajda, Ph. D. (2002), “A chemically induced means of prevention of expected neuronal damage, whose manifestations comprise clinical, cognitive, behavioral, structural, morphometric, electrical, biochemical and molecular biological changes”. Neuroprotection is the mechanism that protects humans from neurodegenerative diseases such as: Alzheimer’s Disease, Parkinson’s Disease, and Amyotrophic Lateral Sclerosis. The main issue is figuring out how estrogen neuroprotection works.
The research reviewed in this paper includes: that there is a specific signaling process that happens in the estrogen receptor-? in astrocytes (glial cell of the central nervous system) (Spence, et al. , 2011), that extra nuclear estrogen receptors induces signaling in the hippocampus that attenuates neuronal injuries and may preserve function (Zhang, et al. , 2010). Estrogen receptors alpha and beta estrogen receptors are the nuclear receptors that can be activated by ligands and accepts estrogens. There are two types : estrogen receptor-? (ER-? ) and estrogen receptor-? (ER-? ). There is not much difference between the receptors.
Literature Review Research has been conducted by Zhang (2010) titled, “Extranuclear Estrogen Receptors Mediate the Neuroprotective Effects of Estrogen in the Rat Hippocampus” at the Experimental and Research Center, North China Coal Medical University, Tangshan, Hebei, People’s Republic of China, and at the Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia, United States of America. Their methods used adult Sprague-Dawley female rats weighting 250-300g that were induced with aneurysm clips to bring about forebrain cerebral ischemia for 10 minutes.
Cerebral ischemia is the process of keeping oxygen from the brain. The rats were then tested with statistical and histochemical analysis. The experiment’s data (Figure 1 below) showed that the surviving neurons from the cerebral ischemia were greater in the rats treated with estradiol than in those not treated. Figure 1: This figure shows that estrogen treatments at the injury site (EDC and E2-BSA) saved about 150 more neurons than the rats that were treated and then also inhibited in estrogen function by ICI (estrogen receptor antagonist).
The research concluded that “…activation of extranuclear estrogen receptors by E2 conjugates EDC and E2-BSA rapidly induces activation of a ERK-Akt-CREB-BDNF signaling pathway and results in neuroprotective and cognitive preserving effects in the hippocampal CA1 region following GCI” (Zhang, 2010). I agree that estrogen neuroprotection rescues neurons from the damages of ischemia. More research was performed by Spence, et al. in 2011 at the Departments of Neurology and Neurobiology, University of California Multiple Sclerosis Program, Los Angeles, CA.
Methods were utilizing genetically modified mice and infecting them with experimental autoimmune encephalomyelitis (EAE) and then sacrificing them for immunohistochemical analysis. EAE is said to closely mimics multiple sclerosis. The data of this experiment shown in figure 2 reveals that estrogen neuroprotection lead to a lower clinical score of EAE than in mice without the estrogen. Figure 2: Mice with estrogen receptor alpha (red and green) received lower clinical scores (lower score equates to less severe disease) than the mice without estrogen receptors (blue and gray) to mediate estrogen neuroprotection.
The research conclusion was: “Our findings show that astrocytes are the principal cells required for mediating the neuroprotective effects of ER-? signaling in an autoimmune CNS inflammatory condition” (Spence, 2011). The conclusion of this research reveals how intense the estrogen neuroprotection is, overall the mice with estrogen neuroprotection has a clinical score around 2. 5 while the mice without estrogen receptor alpha had a higher peak score of about 3. 5. Discussion Both papers had some strengths, weaknesses, and controversy.
Some strengths of the research were using animal testing to learn about estrogen’s neuroprotection and how it specifically works and is carried out and bringing evidence of estrogen’s neuroprotection one step closer to being available in modern medicine. Weaknesses included the sacrifice of many animals and the sparse amount of research on the topic. Controversy comes from some researchers continuing research and coming to different conclusions. Some papers suggest that only ER-a is responsible for neuroprotection and others suggest that astrocytes and neurons are an integral part of estrogen’s neuroprotection.
The discussion continues with the never ending battle of men versus women. The research findings lead us to this question: If estrogen is neuroprotective and more abundant in women, then why are two out of three Alzheimer’s patients women? It would seem that men would have a higher rate of this neurodegenerative disease. Time and life changes seem to have an effect on estrogen neuroprotection. As women get older, their estrogen levels decrease (Mirza , 2010). As men get older their estrogen levels increase. This means that men may be affected by a neurodegenerative disease earlier in life, but women have a higher rate of it at an older age.
According to Vermuelen (2002), plasma concentration values of estradiol in elderly males are significantly higher than in postmenopausal women. Conclusion and Further Research Suggestions for further research include: continue studying ER-? and ER-? signaling pathways to see if ER-? has different or better neuroprotective mechanisms than ER-? and studying astrocyte vs. neuron effectiveness for utilizing estrogen neuroprotection. Also, learning about how to accelerate ER-? signaling to obtain more effective neuroprotection may help propel estrogen neuroprotection in the pharmaceutical realm.
Studying the difference in age of onset for men and women with neurodegenerative diseases in order to determine if women are affected later in life than men would also be a great idea. In conclusion, estrogen neuroprotection should continue to be studied and analyzed. This natural protection from damage to the central nervous system is evident in the research reviewed and needs to be explored for the benefit of organisms. Estrogen neuroprotection is a major aid in keeping male and female organisms alike healthy in various stages of life.