The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs

Abstract

In the slowly progressive neurodegenerative disorders like Parkinson's disease and Alzheimer's disease very different neuronal populations undergo degenerative processes, although the cascades of cellular events leading to death are supposed to be similar. We suggest that the complex pattern of degeneration in Parkinson's disease depends on two processes, a 'primary neurodegeneration' that takes place in the striato-nigral dopamine neurons and a 'secondary degeneration', occurring in distant structures of the basal ganglia network. For the purpose of explaining the regionally different expression of 'primary neurodegeneration' in different diseases, we postulate that the origin of neurodegeneration is associated with the local release of a neurotransmitter. For Parkinson's disease this would mean that the metabolism of dopamine in the striatum, nucleus accumbens and presumably the pedunculopontine tegmental nucleus, together with one or more pathological factors contribute to the initial neurodegeneration. There are recent studies indicating that a transneuronal retrograde degeneration of the substantia nigra pars compacta neurons might be induced by a loss of function of dopaminergic synapses in the striatum. We have recently established an animal model of retrograde striato-nigral degeneration, where the assessment of markers for cellular stress is possible. In Parkinson's disease, several structures distal from the substantia nigra pars compacta undergo neuropathological changes, characterizing the 'secondary neurodegeneration. Our recent studies provide experimental evidence for a chronic cellular stress in these structures because of a relative or absolute glutamatergic overactivity due to the initial loss of dopaminergic innervation. Thus, a loss of dopamine transforms the basal ganglia to a 'destructive network'. Both processes, the 'primary' and 'secondary neurodegeneration', affecting each other, characterize the progress of chronic neurodegeneration. From this point of view, we would further like to develop strategies for symptomatic amendment. Excitatory amino acids seem to be involved not only in the secondary processes of neurodegeneration, but also in initiation of the 'primary degeneration' of the substantia nigra pars compacta. Therefore, a reduction of glutamatergic overactivity constitutes a promising neuroprotective strategy. Especially the new antagonists of the NMDA-receptors with high affinity to the NR2B subunit of the receptor are in focus of our interest, since they reveal a favourable profile of side effects, therefore providing a promising tool for neuroprotection.

Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human

“…This phenomenon was shown in the visual (e.g., Hubel and Wiesel, 1970; Herbin et al, 1999) and olfactory systems (e.g., Pinching and Powell, 1971). Transneuronal degeneration was also shown to damage dopaminergic neurons following striatal lesion (Macaya et al, 1994; Marti et al, 1997; El-Khodor and Burke, 2002; Canudas et al, 2005) and was proposed to contribute to PD (Pedersen and Schmidt, 2000). It was also proposed to occur in other neurodegenerative diseases including Alzheimer's disease and amyotrophic lateral sclerosis (see Fornito et al, 2015).…”

Degree of damage compensation by various pacap treatments in monosodium glutamate-induced retinal degeneration

“…Pathological activation of glutamate receptors is thought to play a key role in neuronal damage in many neurological diseases (Sucher et al, 1997;Smythies, 1999;Pedersen and Schmidt, 2000;Danysz and Parsons, 2002). In the eye, several pathological conditions such as ischemia and some types of glaucoma can be mimicked by experimentally elevating extracellular glutamate concentrations or applying its analogues (Romano et al, 1995;Vidal-Sanz et al, 2000;Osborne et al, 2004).…”

PACAP Improves Functional Outcome in Excitotoxic Retinal Lesion: An Electroretinographic Study

“…Glutamate and its receptors play a key role in many neurological diseases as well as pathological conditions of the eye (Carozzi et al 2008;Danysz and Parsons 2002;Pedersen and Schmidt 2000;Smythies 1999;Sucher et al 1997). Monosodium glutamate (MSG), which can be administered by subcutaneous injection or directly into the eye, leads to the destruction of the inner retinal layers (Babai et al 2005;Chambille and Serviere 1993).…”