Glaucoma as a neuropathy amenable to neuroprotection and immune manipulation

Glaucoma as a neurodegenerative disease

Traditionally, elevation in intraocular pressure (IOP) has been considered to be the main cause of glaucoma (Weinreb and Khaw, 2004); IOP is determined by the balance between secretion and drainage of aqueous humor. In glaucoma, this balance is interrupted, as insufficient fluid drains out of the eye, leading to increased IOP. As a result, the retina and the optic nerve heads are subjected to mechanical (Burgoyne et al., 2005; Sigal et al., 2005), hypoxic (Tezel and Wax, 2004), and oxidative tissue stress (Tezel et al., 2000).

Over the past decades, scientists have focused on the elevated IOP as a primary therapeutic target, trying to diminish this major risk factor (Quigley and Maumenee, 1979; Kass et al., 2002; Leske et al.,

Corresponding author. Tel.: +972 8 934 2467;

Fax: +972 8 934 6018; E-mail: Michal.schwartz@weizmann.ac.il

2003; Johnson et al., 2006; Nickells et al., 2007), while totally disregarding the process of damage that derives from it. Consequently, the current approved glaucoma medications and surgical therapies are directed at lowering IOP, and indeed there are evidences from several clinical trials for a significant attenuation of progressive visual field loss among the treated patients (Quigley and Maumenee, 1979; Heijl et al., 2002; Kass et al., 2002; Leske et al., 2003).

However, some patients continue to suffer from an ongoing visual field loss even after their IOP was effectively controlled (Jay and Allan, 1989; NouriMahdavi et al., 1995; Brubaker, 1996). Even more confusing is the case of normal tension glaucoma (NTG) in which progressive retinal ganglion cell (RGC) death and subsequent glaucomatous damage occurs in the absence of any elevated IOP. Moreover, some studies have reported a negligible relationship between mean IOP and vision loss in glaucoma (Richler et al., 1982; Schulzer et al., 1990;

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Chauhan and Drance, 1992). These observations indicate the possible contribution of IOP-indepen- dent mechanisms to disease progression.

It seems, therefore, that glaucoma is a complex multivariate disease, initiated by several risk factors (with elevated IOP as only one of them), whose individual contributions to glaucomatous destruction have not yet been fully elucidated. As a result, the efforts of researchers have shifted toward understanding and subsequently preventing the disease progression, regardless of the primary cause. Thus, the major goal of glaucoma treatment is moving to neuroprotection, preventing the spread of damage, and protection from the progressive loss of the nerve fiber layers (Schwartz et al., 1996; Schwartz, 2003).

There are many molecular and cellular elements that contribute to the pathological progression and neuronal loss in glaucoma, even after the primary risk factor no longer exists. Following the initial insult, there is a progressive self-perpetuating secondary degeneration of neurons that were spared from the primary injury. This secondary damage is an outcome of the hostile environment produced by the degenerating neurons. The noxious extracellular environment includes mediators of oxidative stress and free radicals, excessive amounts of glutamate and excitotoxicity, increased calcium concentration, deprivation of neurotrophins and growth factors, abnormal accumulation of proteins, and apoptotic signals (Scheme 1), all of which are universal features of many neurodegenerative diseases (Schwartz,

2005). These characteristics place glaucoma among the common neurodegenerative disorders.

Oxidative stress and free radicals

Oxidative stress is involved in the pathogenesis of many neurodegenerative disorders (Beckman et al., 1993; Abe et al., 1995; Giasson et al., 2000; Castegna et al., 2003; Andersen, 2004; Potashkin and Meredith, 2006; Sultana et al., 2006). The central nervous system (CNS) has a unique sensitivity to oxidative stress. Its function requires electrical excitability, transsynaptic chemical connections, and a high metabolic rate, which entail the augmented use of O2 and ATP synthesis. In addition, the CNS lacks an appropriate defense system against the elevated levels of reactive oxygen species (ROS), produced in these tissues. These ROS, accumulating in cells that undergo oxidative stress, react with nitric oxide to produce free radicals, leading to a chain of reactions that result in mitochondrial dysfunction, DNA degradation, and eventually cell death. As in Alzheimer’s disease (Castegna et al., 2003; Sultana et al., 2006), Parkinson’s disease (Giasson et al., 2000), and amyotrophic lateral sclerosis (ALS) (Beckman et al., 1993; Abe et al., 1995), the association of oxidative stress with neurodegeneration has been increasingly reported in glaucoma. Free radicals cause extensive damage to the RGCs and their axons (Oku et al., 1997; Levkovitch-Verbin et al., 2000; Tezel, 2006); they contribute to the secondary degeneration either by a direct neurotoxic effect or indirectly through the induction of glial dysfunction (Tezel and Wax, 2003), oxidative modification of proteins (Tezel et al., 2005), and activation of apoptotic pathways (Martindale and Holbrook, 2002). Oxygen-derived free radicals are therefore an important therapeutic target for treating glaucoma. A variety of antioxidants (Ritch, 2000; Siu et al., 2006) and nitric oxide synthase (NOS) inhibitors (Neufeld et al., 1999) are currently being investigated as potential therapeutic agents.

Excessive glutamate, increased calcium levels, and excitotoxicity

Glutamate is an essential neurotransmitter, participating in a variety of neurological processes in the

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CNS (Sahai, 1990; Lipton and Rosenberg, 1994). It is also the main excitatory neurotransmitter in the retina and is involved in phototransduction (Tsacopoulos et al., 1998).

Excessive levels of glutamate are toxic and detrimental to neurons; an excess of glutamate can hyperactivate the N-methyl-D-aspartate (NMDA) receptor, resulting in a poisonous influx of calcium (Sucher et al., 1997) — a phenomenon termed excitotoxicity (Siliprandi et al., 1992; Dreyer, 1998). In glaucoma, the initially degenerating neurons expel their glutamate stores into the extracellular environment, thereby damaging their still healthy, neighboring neurons. Moreover, Mu¨ller glial cells, which normally take up glutamate, fail to do so in glaucoma (Napper et al., 1999), and thus glutamate levels continue to escalate, leading to RGC death (Olney, 1969; Olney et al., 1986). Excitotoxicity is also common in other neurodegenerative diseases and neurological disorders, including ALS (Van Den Bosch et al., 2006), Alzheimer’s disease (Riederer and Hoyer, 2006; Lipton, 2007), Parkinson’s disease (Beal, 1998; Lancelot and Beal, 1998), stroke, and Huntington’s disease (Choi, 1988b; Lipton and Rosenberg, 1994). Blocking NMDA receptors by a glutamate antagonist can prevent the glaucomatous excitatory damage (Stuiver et al., 1996). However, since glutamate is a fundamental neurotransmitter, vital for the normal maintenance of the retina and essential to many CNS functions (Sahai, 1990), the blockage of its receptor is accompanied by many side effects.

Another approach is to focus on the increased influx of calcium caused by the excess of glutamate and the hyperstimulation of voltage-gated calcium channels (Choi, 1988a, b). Indeed, some calcium channel blockers have been shown to reduce retinal damage (Takahashi et al., 1992; Bath et al., 1996).

Deprivation of neurotrophins and growth factors

Neurotrophins are crucial for the normal maintenance of the CNS. These factors are required by all types of neurons including the RGCs. They are produced in the superior colliculus and lateral geniculate nucleus in the brain and are delivered along the optic nerve to the RGCs. Any