Neuroscience/Objectives/Lecture 12

From PhysioWiki

Mechanisms of CNS injury: Therapeutic targets

Describe features distinguishing ischemic injury in the CNS.

Ischemic insult comes in a variety of forms:

Transient global ischemia

Occurs at the level of the heart (e.g. myocardial infarction) to completely disrupt bloodflow.

Transient focal ischemia

For example, a blood clot may form that temporarily disrupts bloodflow at a particular site. With time, the clot may dissolve and the ischemia may be relieved.

Permanent focal ischemia

For example, permanent clot may form that cannot be dissolved, resulting in permanent ischemia at that site.

In all forms of ischemia:

• No direct mechanical damage
• Neurons and glia die over time even after reperfusion

Discuss mechanisms that have been implicated in secondary injury after ischemic and traumatic injury to the CNS.

Excitotoxicity

Ischemia results in substantial elevation of excitatory amino acid (EAA; e.g. glutamate, kainate, aspartate) levels, which is responsible for secondary neuronal injury (excitotoxicity). Neurons expressing EAA receptors (e.g. the kainate and AMPA receptors) are activated in the presence of high EAA levels, opening Na⁺ and K⁺ channels that result in a rush of ions into the cell. Water follows osmotically, resulting in cell lysis.

In addition, activation of NMDA receptor results in an influx of Ca²⁺ and subsequent activation of Ca²⁺-dependent proteases and onset of other degenerative cascades.

In vitro, secondary injury due to excitotoxicity can be made less severe through treatment with an EAA receptor antagonist. For example, NBQX (an NMDA receptor antagonist) protects against excitatory spinal cord damage by as much as 10-20%. Problems with such therapy include the fact that the window for effective treatment is small (15 minutes to 4 hours), and that because EAAs (e.g. glutamate) are used so extensively by the nervous system that the drugs used to block them have widespread detrimental effects.

Inflammatory and immune responses

Within an hour of traumatic injury, the nervous system—previously thought to be an immune-privileged site—mounts an inflammatory response complete with the release of inflammatory mediators (e.g. prostaglandins, cytokines including IL-1 and TNFα, peptidoleukotrienes, platelet-activating factor, kinins), induction of reactive microglia, and invasion of tissue by leukocytes and platelets. The result is MHC expression, acute phase protein synthesis and acute phase response, complement activation (e.g. anaphylatoxins, membrane-attack complex), expression of adhesion molecules, immune cell invation, and edema.

Necrotic and apoptotic cell death after CNS injury

Cell death after CNS injury occurs through necrosis or apoptosis. The two mechanisms are described below.

Compare and contrast necrosis and apoptosis as forms of cell death in the injured CNS.

Necrosis:

• Loss of membrane integrity
• Morphological signs of organelle damage
• Nuclear flocculation
• Loss of lysosomal content
• Cellular swelling and lysis
• Inflammatory response

Apoptosis:

• Preservation of membrane integrity
• Cytoplasmic, nuclear condensation
• Cleavage of nuclear DNA
• Diminution of cellular volume
• Plasma membrane bleb formation
• Preservation of organellar structure
• Fragmentation into apoptotic bodies, engulfed by phagocytes
• No loss in cellular content
• Does not initiate inflammatory response

Discuss potential therapeutic approaches to CNS injury.

As discussed briefly above, agents that prevent excitotoxicity or inhibit the development of inflammation have been proposed as potential therapeutic courses for CNS injury. Treatments to prevent excitotoxicity include EAA receptor antagonists. Inhibition of inflammation may be done through COX inhibitors, antibodies against cytokines (e.g. TNFα), iNOS inhibitors, complement antagonists, and statins, as well as with other therapies.

Yet another possibility would be replacement of degenerated cells with progenitor cells such as embryonic stem cells. This works better in the brain than in the spinal cord because the brain has endogenous ability to use stem cells (e.g. in the hippocampus and olfactory bulb).

High-dose corticosteroids such as methylprednisolone are also used in the treatment of acute spinal cord injury. However, its use is controversial because of its deleterious side effects and because results of clinical trials have been contradictory.

Finally, it is considerably easier to preserve neurons than to replace them. This the underlying reason that spine stabilization, brain-cooling, etc., is performed following an injury.