Stroke neuronal degeneration

Glutamate that is a major neurotransmitter in the mammalian nervous system not only plays a role in the development of the brain and learning but is also a potent neurotoxin when present in excess at synapses (Plaitakis and Shashidharan, 2000 Rausch et ah, 2006). Glutamate excitotoxicity has been shown to contribute to neuronal degeneration in acute conditions such as stroke, epilepsy, h) oglycemia, and chronic... 

Apoptosis has been implicated in delayed neuronal death associated with many neurodegenerative disorders such as Parkinson s disease, stroke, Huntington s disease, traumatic head injury, Alzheimer s disease, motor neuron degeneration, spinal cord injury, and multiple sclerosis. Since an extensive description of the role of apoptosis in each of these disorders is beyond the scope of the present text, we shall focus on anti-apoptotic strategies for stroke, Parkinson s disease, and multiple sclerosis. 

Recent findings imphcate apoptosis in neuronal degeneration after ischaemic brain injury in animal models of stroke (Mattson et al. 2000). Apoptotic cascades involve increased levels of intraceUular oxyradicals and calcimn induction of expression of proteins such as Par-4 (prostate apoptosis response-4), which act by promoting mitochondrial dysfunction and suppressing antiapoptotic mechanisms mitochondrial membrane depolarisation, calcium uptake, and release of factors (e.g. cytochrome c) that ultimately induce nuclear DNA condensation and fragmentation activation of cysteine proteases of the caspase family activation of transcription factors such as AP-1 that may induce expression of killer genes . 

There are a myriad of known and suspected mechanisms by which diseases can modify chemical neurotransmission. These can vary from no transmission, as in the case of a degenerated or absent neuron, to too much neurotransmission from a malfunction of the synapse. One of the key consequences of loss of neurons in neuro-degenerative disorders such as Parkinson s disease, Huntington s disease, amyotrophic lateral sclerosis (Lou Gehrig s disease), and Alzheimer s disease, is the fact that no neurotransmission occurs subsequent to neuronal loss (Fig. 4—24). This is a conceptually simple mechanism of disease action with profound consequences. It is also at least in part the mechanism of other disorders, such as stroke, multiple sclerosis, and virtually any disorder in which neurons are irreversibly damaged. 

Since no proven effective therapy for neuronal injury, or degeneration, is yet known, and, for example, stroke alone is one of the leading causes of death in many countries, the importance of finding such thereapeutic NMDA antagonists is self-evident. It will be important to determine whether certain NMDA antagonists are more effective or have fewer side effects than others in specific disease states. 

Neoplasms or strokes in the regions of the nigrostriatal pathways Traumatic lesions interrupting substantia nigra projections Normal-pressure hydrocephalus Parkinsonism with other neuronal system degenerations Wilson s disease (copper deposition in the brain)... 

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