Glutamatergic Overactivity Research Articles

The neuroprotectant properties of glutamate antagonists and antiglutamatergic drugs.

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.

Excitatory amino acids and memory: Evidence from research on Alzheimer's disease and behavioral pharmacology

The excitatory amino acid transmitter (EAA) system is believed to play a crucial role in a variety of physiological processes related to neuronal plasticity. Substantial neurophysiological evidence suggests that, under normal physiological conditions. EAAs may be involved in mechanisms underlying learning and memory. However, overactivity of this system produces excitotoxic damage to neurons which is believed to be an etiological factor in various neurological conditions, such as epilepsy, and stroke-induced impairments. The fact that EAAs have been implicated in both, normal cognitive function and in degenerative neurological conditions suggests that they may contribute to the etiology of Alzheimer's disease (AD), because AD is characterized by memory deficits and specific histopathological signs of neuronal damage. This paper summarizes information regarding 1) the involvement of EAAs in Alzheimer's disease and 2) results from psychopharmacological studies of EAAs in laboratory animal models of learning. Investigations of the pathophysiology of AD indicate that glutamatergic deficits are associated with this syndrome. However, there is controversy concerning the nature of this defect. As a result, it is unclear whether it is a consequence of excitotoxic changes produced by glutamatergic overactivity or result from a decrease in glutamatergic function. Evidence from behavioral studies is consistent with the conclusion that EAAs may be involved in the acquisition of conditioned responses. However, in parallel with the clinical findings, learning impairments have been produced by treatments which either increase or decrease activity within this transmitter system. Therefore, although present results suggest that the EAAs play a role in cognition and in clinical syndromes in which such function is compromised, the specific nature of that role needs to be elucidated by future research.