**6. Conclusion**

*Neuroprotection - New Approaches and Prospects*

response of the tissue exposed to SERMs [238, 239].

Afterwards, using ER-α and ER-β agonist (PPT and DPN, respectively) without 17β-estradiol treatment, results showed neuroprotection was mimicked by PPT and suggested that ER-α regulates this protective effect [235]. Likewise, in a model of astrocytic cells it was found that estradiol improved in one of the HI conditions, parameters such as cell viability, mitochondrial membrane potential, reduced ROS production and prevented the loss of mitochondrial mass [38]. Nevertheless, estrogen use can have detrimental effects like the augment in the incidence of breast and uterus cancer [12–14]. In order to maintain the benefits and avoid these side effects, other drugs have been developed, mainly SERMs and STEARs [12–14]. The mechanism of regulation of the SERMs that determines either if they act as agonist or antagonist in an specific cell type depends on the predominant subtype of estrogen receptor alpha or beta. In addition, the co-activators, co- factors and helper proteins of each cell will determine the kind of the

In a MCAO rat model, neurogenesis in the ipsilateral subventricular zone (SVZ) after ischemia was significantly higher in estrogen and raloxifene-treated animals compared to rats treated with placebo. Otherwhise, tamoxifen did not show this enhancing effect on neurogenesis. However, both SERMs tamoxifen and raloxifene as well as estrogen, significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia [240]. On the other hand, tibolone action is given by the metabolization of the tibolone to three different metabolites (delta-4 tibolone; alpha-hydroxy tibolone and 3- beta-hydroxy tibolone). Each of them produces different responses. Delta-4 tibolone is an agonist to the androgen receptor and the progesterone receptor, meanwhile alpha-hidroxy and beta-hidroxy tibolone are antagonists of those receptors but agonists of the ER [241]. Keeping this in mind, Avila-Rodriguez et al. (2014) found out that tibolone ameliorates the effects of the GD on an in vitro model of astrocytes, making this molecules interesting for further research in a OGD model [12]. For this reason, in recent years we have been working on the implementation of these neuroprotection strategies in an astrocyte model using Raloxifene as a neuroprotector in the OGD model. **Figures 3** and **4** show the

**228**

**Figure 4.** *Mitochondrial mass.*

The different pathologies in which the HI events and with these, the oxygen and glucose deprivation are present, have been shown to exert a high impact on society. Over the years, a multitude of efforts have been directed towards the search for effective treatments that counteract the damage caused by these conditions. The different neuroprotection targets try to combat specific points of damage caused by hypoxia, including oxidative stress, dysregulation of the cell cycle and energy homeostasis [242]. Both in the initial damage phase and in the final one, the different neuroprotective agents may have anti-inflammatory, antioxidant, anti-excitotoxicity or anti-apoptotic capacities [243]. However, due to the complex network of factors that influence these pathologies, such as the cellular interactions (molecular, biochemical, protein, etc.) inherent to the CNS, as well as the genderdependent response [236] to the use of these neuroprotective agents, the success in the treatments has not been optimal [7]. Estradiol treatment not only prevents neuronal damage, but may also limit the neurodegenerative modifications induced by HI in the early stage of development. The development of SERMs and STEARs brings with it a range of possibilities for the treatment of HI, due to its advantages, focused on the nervous system without having side effects. However, it is necessary to develop new generations of these compounds to improve their neuroprotective effects. Further research is necessary to provide new alternatives in the implementation of new therapeutic strategies and novel approaches.

*Neuroprotection - New Approaches and Prospects*
