Neurochemical Aspects of Neurotraumatic and Neurodegenerative Diseases

Neurodegeneration is defined as a process that results in death of neural cells (neurons, astrocytes, and oligodendrocytes) in acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases. Neurodegenerative diseases are a complex heterogeneous group of diseases associated with site-specific premature and slow death of certain neuronal populations in brain and spinal cord tissues. For example, in Alzheimer disease (AD) neuronal degeneration occurs in the nucleus basalis, whereas in Parkinson disease (PD) neurons die in the substantia nigra. The most severely affected neurons in Huntington disease (HD) are striatal medium spiny neurons. Although in ischemic injury neurons die in several regions, the CA1 hippocampal region is relatively more susceptible to ischemic injury compared to other regions. The neuronal populations that are lost in ischemic injury and neurodegenerative diseases modulate functions, such as controlling movements, processing sensory information, memory, and making decisions.

Collectively, neurodegenerative diseases are characterized by chronic and progressive loss of neurons in discrete areas of the brain, producing debilitating symptoms such as dementia, loss of memory, loss of sensory or motor capability, decreased overall quality of life eventually leading to premature death. Two types of cell death are known to occur during neurodegeneration: (a) apoptosis and (b) necrosis. The necrosis is characterized by the passive cell swelling, intense mitochondrial damage with rapid loss of ATP, alterations in neural membrane permeability, high calcium influx, and disruption of ion homeostasis. This type of cell death leads to membrane lysis and release of intracellular components that induce inflammatory reactions. Necrotic cell death normally occurs at the core of injury site. In contrast, apoptosis is an active process in which caspases (a group of endoproteases with specificity for aspartate residues in protein) are stimulated. Apoptotic cell death is accompanied by cell shrinkage, dynamic membrane blebbing, chromatin condensation, DNA laddering, loss of phospholipids asymmetry, low ATP levels, and mild calcium overload. This type of cell death normally occurs in penumbral region at the ischemic injury site and in different regions in various neurodegenerative diseases.

Thus, apoptosis and necrosis are two extremes of a wide spectrum of cell death processes with different mechanistic and morphological features. However, they may share some common mediators and signal transduction processes that are often inseparable. Although the molecular mechanism of neurodegeneration remains unknown, it is becoming increasingly evident that excitotoxicity, inflammation, and oxidative stress may contribute to neural cell demise independently or synergistically. During aging an upregulation of interplay (cross talk) among exicitotoxicity, oxidative stress, and neuroinflammation occurs throughout the normal elderly brain, but in neurodegenerative diseases this interplay turns on specific genes that affect only a specific neuronal population in a particular region where neuronal degeneration occurs both by apoptotic and necrotic cell death.