Excellent review of the rationale for use of memantine in AIDS-dementia complex - found at:
pano.com
Approximately half of children and one-third of adults with the acquired immunodeficiency syndrome (AIDS) eventually develop neurological manifestations, including dysfunction of cognition, movement and sensation, often resulting in frank dementia. The enigma has been that these abnormalities can occur in the virtual absence of neuronal infection by the human immunodeficiency virus type 1 (HIV-1) and in the absence of superimposed malignancy or opportunistic infections (e.g., cytomegalovirus or toxoplasmosis). Recent evidence suggests that HIV-infected macrophages or gp120-stimulated macrophages release toxins that cause neuronal damage in AIDS patients with neurological manifestations (Giulian et al., 1990; Pulliam et al., 1991; Lipton, 1992; Toggas et al., 1993). Neuronal injury in vitro due to HIV-infected macrophages or gp120-stimulated macrophages was shown to be ameliorated by antagonists of the N-methyl-D-aspartate type of glutamate receptor in the brain (Giulian et al., 1990; Lipton et al., 1990; Lipton et al., 1991; Lipton, 1992; Müller et al., 1992; Savio and Levi, 1993). Recently, data obtained in an in vivo rat model of gp120-induced neuronal damage has also been shown that NMDA antagonists can attenuate the lesions (Lipton and Jensen, 1992). Of the known NMDA open-channel blockers, memantine is a prime candidate for clinical trials to combat neurological disorders, such as HIV-associated cognitive/motor complex (or the AIDS dementia complex), that have a component of NMDA receptor-mediated neurotoxicity.
The level of memantine (2-12mM) achieved in the human brain during treatment for Parkinson's disease (Wesemann et al., 1980) can afford protection from NMDA receptor-mediated neurotoxicity both in vitro and in vivo (Seif el Nasr et al., 1990; Erdo and Schafer, 1991; Chen et al., 1992; Keilhoff and Wolf, 1992; Osborne and Quack, 1992). The pathogenesis of CNS disease during HIV-1 infection relates to infection of brain macrophages and microglia that produce high levels of various neurotoxins including TNF, IL1beta, arachidonate metabolites and PAF (Genis et al., 1992). Gelbard et al., (1994) demonstrated that memantine attenuates the neurotoxic effects of PAD. Recently, the Lipton laboratory at Harvard and a laboratory in Germany
found that low micromolar levels of memantine can protect neurons from damage induced by gp120 in vitro (Lipton, 1992; Muller et al., 1992) and in vivo in an animal model (Lipton and Jensen, 1992). These findings raise the possibility that this clinically-tolerated NMDA antagonist, memantine, might be useful in the treatment or prevention of the AIDS dementia complex (Lipton, 1993).
As many as two thirds of AIDS patients develop signs of HIV-associated cognitive/motor complex dysfunction (of which a severe form is the AIDS dementia complex) (Price et al, 1988). In addition to white matter (axon and myelin) damage in AIDS brains, a 20-50% loss of certain neuronal populations has been reported in areas including the cortex and retina (Ketzler et al, 1990; Wiley et al, 1991; Tenhual et al, 1990; Dreyer et al, 1990, Lipton et al, 1991). Neurons are apparently not infected and the envelop protein, gp120 is toxic probably via activation of macrophages or microglia. At the present time only palliative therapy is available for HIV CNS dysfunction: no therapy is specifically directed toward attenuation of HIV-associated neurodegeneration.
HIV infection of the human CNS initiates a pathogenic cascade that results in elevated levels of glutamate and reactive nitrogen intermediates that activate the NMDA receptor leading to increased calcium flux and neurodegeneration (Lipton and Rosenberg, 1994). There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels (see Lipton and Gendelman, 1995). |
