Antioxidants In Neuroprotection In Vitro

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Antioxidant therapies are discussed for a variety of neurodegenerative disorders such as Parkinson's disease, ischemia, and other age-related disorders in general (3,37,38). Numerous free radical scavengers have been tested for their neuropro-

tective potential in vitro and in vivo. The most prominent lipophilic antioxidant is vitamin E which has not only a protective activity against Ap toxicity, but also against other oxidative challenges such as glutamate (33). On the other hand, it is known that vitamin E does not easily pass the blood-brain barrier, which makes it hard to enrich a powerful antioxidant in brain tissue in general (39). Therefore, the search for antioxidants with an increased permeability for endothelial tissues is very important and may lead to more effective antioxidant neuroprotection. Among the various other compounds that have been tested for an antioxidant activity against Ap toxicity or glutamate toxicity in vitro is also the pineal hormone melatonin, the 21-aminosteroids (lazaroids), and the prominent glucocorticoid and progesterone receptor antagonist RU 486 (mifepristone) (25,40,41).

A. Estrogen as Free Radical Scavenger

There are numerous links between the female sex hormone estrogen and neurode-generative diseases in general and AD in particular. It is well known that women are twice as likely to develop AD than men (42,43) and that the loss of estrogens during menopause may play a role in an age-associated cognitive decline (44). Increasing the level of estrogens by estrogen replacement therapy may lower the risk of getting AD for postmenopausal women (45,46). Estrogen is a steroidal compound that binds to cognate receptors upon penetration of the cellular membrane, and these activated estrogen receptors comprise transcription factors that translocate into the nucleus. There estrogen receptors bind to estrogen-responsive elements in the promoter regions of certain target genes activating the transcription of these genes. It is known that estrogen affects neurons through this estrogen receptor-dependent hormonal effect by activating the transcription of certain receptors of neurotrophins such as nerve growth factor (NGF) (47). Therefore, estrogens may have a neuroprotective effect due to the increase of intrinsic neuro-trophic activities.

Furthermore, it has been shown that estrogens can modulate neurotransmit-ter receptors and may also regulate synapse formation during nerve system development and regeneration. Recently, it has been shown that estrogens also have a modulatory effect on the metabolism of the AD-associated amyloid p-protein precursor. Estrogens increase the so-called nonamyloidogenic pathway of APP processing and therefore decrease the secretion of potential neurotoxic Ap fragments as they are found in an aggregated form in senile plaque deposit (48,49). In addition to these estrogen effects that are depending on estrogen receptor activation, estrogens may also have nonreceptor-mediated modulatory effects on neurons. Recently, it has been demonstrated that estrogens can modulate the activity of the 5HT3 receptors independently from estrogen receptor activation (50).

Another recently discovered receptor-independent activity of estrogen is its role as antioxidant. The steroidal compound estrogen has been shown to prevent oxidative nerve cell death as caused by amyloid P protein, hydrogen peroxide, or glutamate (51). This antioxidant activity of estrogen is due to its chemical structure and is independent of estrogen receptor activation. Several estrogen derivatives have been tested for their protective activity in paradigms of oxidative nerve cell death and it has been found that other estrogens, such as estriol, estrone, ethinylestradiol, 2-hydroxyestradiol, and 4-hydroxyestradiol, also have powerful antioxidant effects. Oxidative cell death could be prevented in primary neurons as well as in clonal hippocampal cells and in differentiated tissue using organo-typical slices. In summary, the basic prerequisites for estrogenic molecules to act as antioxidants and neuroprotectants against oxidations is the presence of the intact hydroxyl group on ring A of the steroidal compound (Fig. 1). Whenever this hydroxyl group is modified such as through an ether modification as in mestranol (methyl ether), the protective activity and the lipid peroxidation inhibiting activity of the compound is lost (52). The same is true for the molecule a-tocopherol (vitamin E) since in tocopherol acetate and other derivatives the antioxidant activity is almost completely lost.

A comparison of the basic structure of estrogen and vitamin E clearly shows that there are common features. Both molecules consist of a large lipophilic structure conferring the ability to penetrate and accumulate in the neuronal cell membrane. Moreover, both molecules carry an intact hydroxyl group linked to an aromatic system comprising a phenolic structure. With respect to the structure of these molecules, vitamin E and estrogens are therefore quite similar, although the potency of the antioxidant activity is different.

The major disadvantage of using estrogen as antioxidant with respect to a potential clinical use obviously is its hormonal effects that are mediated through estrogen receptors. Although for women, the application of estrogens may be envisaged specifically in conditions when estrogen levels drop. Of course, in men such a hormone cannot be used. More recent data show that estrogen can be degraded structurally into compounds that carry only selected structural characteristics of estrogen or vitamin E. Such compounds comprise the group of aromatic alcohols (53).

B. Aromatic Alcohols and the Basic Structure of a Phenolic Antioxidant

Using liver microsomes, it was previously shown that naturally occurring phenolic compounds may potentially prevent peroxidative damage (54-56). When using aromatic alcohols with a phenolic group linked to a lipophilic side chain, the antioxidant activity of estrogen can be mimicked. A compound such as 4-dodecylphenol has a similar antioxidant and neuroprotective activity as 17p-estra-diol.

17beta-estradiol no'^^^f

0H I quercetin

17beta-estradiol no'^^^f

0H I quercetin

mestranol 2-naphthol 2-methoxynaphlhalene

Rl, R2 = H : delta-tocopherol N-acetylserotonin melatonin

Figure 1 Structures of various phenolic structures tested for potential antioxidant activities.

Rl, R2 = H : delta-tocopherol N-acetylserotonin melatonin

Figure 1 Structures of various phenolic structures tested for potential antioxidant activities.

A second row of examples with neuroprotective activity consists of the group of indole derivatives such as 5-hydroxytryptamine (serotonin) and N-ace-tyl-5-hydroxytryptamine (normelatonin). Whenever the phenolic group is altered and the hydroxyl group modified such as in N-acetyl-5-methoxytryptamine (melatonin), the antioxidant capacity is decreased or lost. This might explain the fact that melatonin when used as an antioxidant in vitro has to be used in rather high concentrations (up to 1 mM) in order to get a significant protection, whereas its precursor molecule, N-acetyl-5-hydroxytryptamine (normelatonin), has much higher antioxidant and neuroprotective capacity (Table 1).

Another example further confirming the concept of aromatic alcohols as potential basic structure for antioxidants is 2-naphthol. 2-Naphthol protects clonal mouse hippocampal HT22 cells against glutamate or H2O2, but its derivative me-thoxynaphthalene does not prevent oxidative cell death (53). Therefore, in general, it can be summarized that a phenolic structure and a lipophilic side chain are the minimal requirements for one class of potential antioxidant drugs that

Table 1 Protection of Clonal Hippocampal HT22 Cells from Mouse Against Oxidative Glutamate Toxicitya

Control 100% Viability

5 mM glutamate alone 5 ± 3

5 mM glutamate/pretreatment with 1 |lM 5 |lM 20 |lM 200 |lM

Control 100% Viability

5 mM glutamate alone 5 ± 3

5 mM glutamate/pretreatment with 1 |lM 5 |lM 20 |lM 200 |lM

17P-Estradiol

9 ± 3

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