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In recent years, evidence shows that Estrogen has neuroprotective effect on the brain. Many studies are now being conducted to determine if Estrogen can be used to treat Traumatic brain injury (TBI), a leading cause of fatalities amongst youth. Estrogen is found at a higher concentration in men than in women, therefore studies are also investigating if the neuroprotection is higher in females than in males. Neuroprotection was observed in male animal models who were subjected to Estrogen pre-stroke and post-stroke. A combination of Estrogen and Progesterone seem to induce a higher level of neuroprotection. Animal models exposed to both estrogen and progesterone showed an improvement in scores after TBI. This review will discuss the neuroprotective aspects of Estrogen and also examine evidence that the estrogen can aid in neuro- and cyto-genesis following a mechanical brain injury. The review will also the address further directions these studies can take.
In a clinical study conducted to determine if the pregnant women have a better outcome after TBI, a group of 1800 female patients with moderate to severe TBI were studied and of these patients 71 were pregnant (Berry et al., 2011). Patients between the ages of 25 and 50 were observed, other than a lower systolic blood pressure in younger patients, there was no difference between pregnant and non pregnant TBI patients (Berry et al., 2011). The Pregnant TBI patients showed an increase in mortality despite the adjusting the confounding variables (Berry et al., 2011). Since all of the pregnant TBI patients were within the age range of 14-57, another analysis was conducted, after adjusting the confounding variables this group showed and increasing trend in the mortality as well (Berry et al., 2011). They discovered a decrease in mortality of premenopausal women between the ages of 14 and 44; and in age matched males both females and males under the age of 50, showed similar mortality rate (Berry et al., 2011).
The data presented in this study showed that the there was no difference between non pregnant and pregnant TBI patients (Berry et al., 2011). These results were contradicting other study which showed that Estrogen was neuroprotective (Berry et al., 2011). Considering that this is the first study conducted on the role of sex steroids in pregnant women with TBI, the authors discussed their results adequately (Berry et al., 2011). However, they have made a lot of assumptions regarding the state of the women i.e. whether or not they have used contraceptive or the hormonal status of both the groups which might have affected their data (Berry et al., 2011).
In the study, Neuroprotective Anti-Apoptosis Effect of Estrogens in Traumatic Brain Injury, rats were used as an animal model. The dynamic cortical deformation (DCD), an effective method of causing TBI lesions was used (Soustiel et al., 2005). These rats were anesthetized and a burr hole was surgically drilled in the left parietal region and a hollow screw was connected to it (Soustiel et al., 2005). Another incision was made above the spine and an osmotic pump with conjugated Estrogen was inserted (Soustiel et al., 2005). On the fourth day the brains were surgically removed and were embedded in paraffin which was stained using in situ cell death detection kit (Soustiel et al., 2005). In order to conduct the bcl protein analysis, the paraffin sections were re-stained and observed under a light microscope and the results were recorded (Soustiel et al., 2005).
A significant reduction of apoptosis was recorded in the first two perilesional layer rats treated with Estrogen (Soustiel et al., 2005).The Bcl protein analysis showed a significantly higher expression of bcl-2 in rats exposed to Estrogen (Soustiel et al., 2005). In estrogen exposed rats, TUNEL doublestaning and synaptophisisn resulted in a lower number of TUNEL-positive cells (Soustiel et al., 2005). The authors thoroughly stated all of their findings and also addressed other hypotheses.
In "Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury" water content of the brain was measure in the control, sham and vehicle groups were measured (Shahrokhi et al., 2010). 50 albino Wistar rats were used; the control group were not drugged and had intact ovaries, sham group were not drugged, OVXed 2 weeks before the experiment and underwent false trauma under anesthesia, the vehicle group underwent an induced brain injury after OVX and equal part of the vehicle, sesame oil were given (Shahrokhi et al., 2010).
The Estrogen group was exposed to pharmacological dose of Estrogen after the induced brain injury caused 2 weeks after OVX, the Progesterone group were similar to the Estrogen group except that they were give a pharmacological dose of Progesterone (Shahrokhi et al., 2010). Data collected showed a decrease in water content in the brain in both the Estrogen and Progesterone groups when compared to the vehicle group (Shahrokhi et al., 2010). ICP levels checked twenty-four hours after TBI, and were found to be lower in both the Estrogen and Progesterone groups when compared to the vehicle group (Shahrokhi et al., 2010). The CPP levels were checked twenty-four hours after TBI and showed an increase in both the Estrogen and Progesterone groups when compared to the vehicle group (Shahrokhi et al., 2010). The author adequately discussed the results and clearly list possible interpretations.
In the study "Intracerebral Estrogen Provision Increases Cytogenesis and Neurogenesis in the Injured Zebra Finch Brain" used adult male Zebra Finches as an animal model. Two experiments were conducted over the course of the study; the first experiment was Effect of Local Aromatase Inhibition on Cytogenesis, Neurogenesis, and Neuronal Morphogenesis (Walter et al., 2010). In this experiment cytogenesis induced by brain injury was measure based on the BrdU positive cells per unit; collapsing across the FAD and SSV hemispheres, injury cite showed the highest amount of cytogenesis and VSVZ had the lowest amount (Walter et al., 2010). Neurogenesis was measured based on the mean of BrdU and Hu double positive cells observed per image (Walter et al., 2010). Neurogenesis was highest in the INJ and lowest in the VSVZ (Walter et al., 2010).
In the second experiment, after administering E2 locally, INJ had the highest level of cytogenesis and VSVZ the lowest (Walter et al., 2010). FAD +E2 treated areas were seen to have a higher level of neurogenesis INJ had the highest level of neurogenesis and VSVZ the lowest (Walter et al., 2010).
In "Estrogen-induced recovery of autonomic function after middle cerebral artery occlusion in male rats" 46 Sprague-Dawley male rats between 200-250g were used (Saleh et al., 2001). Rectal temperature was maintained throughout the experiment, the collected data showed that the in animals who were subjected to intravenous Estrogen 30 minutes before or immediately following MCAO blocked the increase in RSNA completely (Saleh et al., 2001).
RSNA and VPNA levels were restored to pre-stroke values when Estrogen was given 30 minutes after MCAO (Saleh et al., 2001). An injection of estrogen receptor antagonist ICI-
182,780 + estrogen prevented the decline of VPNA (Saleh et al., 2001). The author adequately explains the results and takes into consideration most situations such as atrial pressure and heart rate before MCAO.
Synthesis/ Analysis and Conclusions:
Summary, Overall Impression and Future Direction
Estrogen is shown to have neuroprotective effect during a brain injury. However there are certain studies such as the one conducted using pregnant women with moderate to severe TBI showed no neuroprotection (Berry et al., 2011). In order solve this contradiction, further studies need to be conducted on pregnant women with TBI and these studies need to analyze effect of other factors such as environment which may interfere with Estrogen's neuroprotection.
Progesterone also seems to have a neuroprotective effect during brain injury (Shahrokhi et al., 2010). Further studies need to be conducted to compare neuroprotection of both Estrogen and Progesterone. Study should also determine if a combination of Estrogen and Progesterone is better than administering only one of these hormones.
Berry C., Ley E.J., Mirocha J., Margulies D.R., Tillou A., Salim A., 2011. Do pregnant women have improved outcomes after traumatic brain injury?. Am J Surg. 201, 429-432.
Saleh T. M., Cribb A. E., Connell B. J., 2001. Estrogen-induced recovery of autonomic function after middle cerebral artery occlusion in male rats. Am J Physiol Regulatory Integrative Comp Physiol. 281, R1531-R1539.
Shahrokhi N., Khaksari M., Soltani Z., Mahmoodi M., Nakhaee N., 2010. Effect of sex steroid hormones on brain edema, intracranial pressure, and neurologic outcomes after traumatic brain injury. Can. J. Physiol. Pharmacol. 88, 414-421.
Soustiel J. F., Palzur E., Nevo O., Thaler I., Vlodavsky E., 2005. Neuroprotective Anti-Apoptosis Effect of Estrogens in Traumatic Brain Injury. J Neurotrauma. 22, 345-352.
Walters B.J., Alexiades N.G., Saldanha C.J., 2010. Intracerebral Estrogen Provision Increases Cytogenesis and Neurogenesis in the Injured Zebra Finch Brain. Developmental Neurobiology. 71,Â 170-181.