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probably caused by the reduced biosynthesis of glutamate receptors (Martin et al., 2002). Indeed, reactive glial cells can exacerbate neuronal damage through the release of cytokines, ROS, or NO (Kuehn et al., 2005). Another glial cell-mediated apoptotic stimulus is tumor necrosis factor-alpha (TNF-a). This proinflammatory cytokine is synthesized by retinal glia in glaucoma and, when bound to its receptor, which is present on RGCs, can induce apoptosis through a caspase-mediated pathway (Tezel et al., 2001).

Glutamate is a central nervous system excitatory neurotransmitter and has a central role in the conduction of signals between neurons. However, high extracellular levels of glutamate can induce neuronal cell death by excitotoxicity (Choi, 1988). This phenomenon, which was identified in the retina in 1957, concerns all the neurons of the nervous system: it is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death (Lucas and Newhouse, 1957).

There are three main types of glutamate receptors: N-methyl-D-aspartate (NMDA) receptors, kainate receptors, and alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The most extensively studied are the NMDA receptors, which are essential for normal neuronal function. Excitotoxic neuronal cell death is mediated in part by overactivation of NMDA glutamate receptors, and results in excessive Ca2+ influx through the ion channel associated to the receptor. An increase in intracellular Ca2+ can activate endonuclease and protease, which can kill the cell (Dreyer et al., 1995). Moreover, neurotoxicity is partly mediated by ROS; indeed, NMDA-induced ROS production depends on extracellular Ca2+, a finding which supports the hypothesis that uncoupling of neuronal mitochondrial electron transport may elicit signals that are dangerous for cell survival (Dugan et al., 1995). The voltage-dependent calcium channels (VDCC) control the intracellular inflow of Ca2+ (Hofmann et al., 1994). Both ischemia and glutamate cause an increase of inflow of calcium to the cell. Nevertheless, in glaucoma, the role of glutamate excitotoxicity remains unclear, not least because RGCs are relatively resistant to

glutamate excitotoxicity in the presence of neurotrophic factors (Ullian et al., 2004).

Even if intracellular signals that lead to RGCs death are not known, it is possible that they might be similar to those observed in other types of neurons. Free radical production can trigger lipid peroxidation, causing the destruction of cell membranes and activation of NO, which is in turn a neurotoxin (Neufeld, 1999). Furthermore, the involvement of both glutamate receptors and oxidative stress has been implicated in neuronal damage due to the impairment of energy metabolism (AGIS, 2000). Oxidative stress increases the Na+ concentration in Ca2+-free medium by an Na+-dependent process entry through L-type voltage-sensitive calcium channels. The increased permeability of L-type voltage-sensitive calcium channels to Na+ may increase the Ca2+-indepen- dent release of endogenous glutamate which, by activating NMDA, induces the release of GABA by reversal of its transporter. The equilibrium between the release of GABA and glutamate may play an important role in neuroprotection against excitotoxic attack (Agostinho et al., 1997a). Furthermore, oxidative stress causes long-lasting modifications of the glutamate/aspartate transport system and excessive activation of glutamate receptors, thereby increasing the influx of Na+ and maintaining Na+ intracellular concentration (Agostinho et al., 1997b, 1996). Moreover, in conditions of oxidative stress, the release of aspartate, glutamate, and GABA, occurring through the reversal of the Na+-dependent transporters, is associated with the impairment of energy metabolism (Rego et al., 1996). Finally, the GSH system is important in protecting neurons during inhibition of energy metabolism. The oxidative challenge during energy inhibition is not solely a downstream consequence of glutamate receptor overstimulation (Zeevalk et al., 1998).

Therapeutic and preventive substances of interest in glaucoma

Although reducing IOP remains the primary goal of POAG therapy, the aim of glaucoma therapy should be to facilitate the survival of RGCs in that

neuroprotection could limit and/or prevent damage by stopping the mechanisms that lead to RGCs death.

Moreno et al. (2004) found a significant decrease in the activity of the antioxidant defense system in the retinas of rats with experimental glaucoma and suggested that the manipulation of intracellular redox status by means of antioxidants might be a new therapeutic tool for preventing glaucomatous cell death.

Better knowledge of the pathogenesis has opened up new therapeutic approaches that are often referred to as non-IOP-lowering treatment. These new agents, some of which are still under investigation, can improve the oxidative stress impact.

Ginkgo biloba extract

Ginkgo biloba extract (GBE) contains over 60 known bioactive compounds, including flavonoids, cyanidins, and other uncharacterized compounds (Defeudis, 2002). The mechanism of action of the active components of Ginkgo biloba is unknown (Ritch, 2000). GBE exerts significant protective effects against free radical damage and lipid peroxidation in various tissues, and has been found to be more effective than water-soluble antioxidants (Ko¨se and Dogan, 1995). Its antioxidant potential is comparable to that of substances such as alpha-tocopherol and retinol acetate (Ko¨se and Dogan, 1995). Indeed, GBE appears to protect brain neurons suffering from oxidative stress can scavenge nitric oxide and possibly inhibit its production (Marcocci et al., 1994; Oyama et al., 1994; Kobuchi et al., 1997). Furthermore, GBE improves both peripheral and cerebral blood flow, induces a dose-dependent contractile or relaxing effect on vascular smooth muscle, and has neuroprotective properties in conditions such as hypoxia or ischemia, cerebral edema, and peripheral nerve damage (Oyama et al., 1994; Ritch, 2000). Rats treated with GBE suffer less RGC loss than control animals with similar IOPs (Hirooka et al., 2004). Moreover, GBE has also been used in patients with normaltension glaucoma to improve automated visualfield indices (Quaranta et al., 2003).

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Green tea

Tea consumption may be linked to low incidences of various pathological conditions, including cardiovascular disease, diabetes, obesity, and cancer. Green tea is rich in polyphenols. The principal active polyphenols in green tea are epigallocatechin gallate, epigallocatechin, and epicatechin, with epigallocatechin gallate being the most abundant (Yang et al., 2000). Epigallocatechin gallate and epigallocatechin have the highest radical scavenging activity (Henning et al., 2003). Tea flavonoids (catechins) have been reported to possess divalent metal-chelating, antioxidant and anti-inflammatory activities, to penetrate the blood-brain barrier and to prevent neuronal death in a wide array of cellular and animal models of neurological diseases (Mandel et al., 2006). Catechins might be effective in minimizing IR injury (Van Jaarsveld et al., 1996). Although clinical evidence is still limited, green tea polyphenols may protect against neurodegenerative diseases.

Ginseng

Panax ginseng, a herbal medicine used worldwide, possesses different chemical characteristics in its underground and aerial parts. It has antiallergic properties and antineoplastic and immunomodulatory effects (Choo et al., 2003; Joo et al., 2005). The main components responsible for the actions of ginseng are ginsenosides, which have been shown to affect several ion channels found at preand postsynaptic sites in the nervous system, including voltage-dependent Ca2+ and Na+ channels, and nicotinic acetylcholine and NMDA receptors (Kim et al., 2002, 2005). Of greater interest are the ginsenoside saponins Rb1 and Rg3, which attenuate or inhibit responses that lead to the apoptotic cascade, including glutamateinduced neurotoxicity, calcium influx into cells in the presence of excess glutamate, and lipid peroxidation (Ritch, 2005). Moreover, Rb1 ginsenoside stimulates NOS activity in a concentrationdependent manner and reduces cardiac contractility (Scott et al., 2001). Recently, it has been shown that ginsenosides Rb1 and Rg1 play a partial neurotrophic and neuroprotective role in