9. Theories of brain cell damage Glutamate toxicity Calcium Neuro toxicity Calcium Activated Proteases and Endo-nucleases Necrosis and apoptosis Nitric oxide formation Mitochondrial dysfunction Formation of free radical species [ROS]
10. Theories of brain cell damage AMPA and NMDA are 2 types of ionotropic glutamate receptors: (AMPA =amino-3-hydroxy-5-methol-4-isoazole propionic acid) (NMDA = N-methyl –D- aspartate)
11. Schematic ischaemic cascade When the presynaptic neurone becomes ischaemic, it depolarizes opening up the Na & K channels[1,2]
12. Schematic ischaemic cascade This leads to opening of Ca channels and influx of calcium into the pre synaptic area [3]
13. Schematic ischaemic cascade In addition, the pre synaptic area releases glutamate that activates the NMDA, AMPA and MGLUR [4.5.6.7.8] This causes entry of calcium in the post synaptic area
14. Schematic ischaemic cascade This causes Nitric oxide levels to increase and ↑ perfusion. The released calcium activates various enzymes.
15. Schematic ischaemic cascade Reperfusion occurs [9] and upregulated adhesion molecules cause release of cytokines to cause inflammation [10] . Inflammation leads to release of free radicals like ROS [11] -> cell death
23. ROS induced cell damage ROS Inactivate & damage critical memb. Proteins like Na + & Ca ++ pumps, creatin kinase, mitochondrial superoxidase Calpain mediated proteolysis Oxidation of Na+ K+ ATPase exchanger Protein side chain oxidation Glycosylic bond cleavage ROS Nucleic acid damage by Chemical modification of nucleic acid base Crosslinking of protein to DNA strand ROS Nucleic acid elongation, altered DNA coding Impaired DNA replication & transcription Cell death Lipid peroxidation (fatty acid oxidation
46. Neuroprotection could help limit the damage caused by stroke Reference 1. Fisher M. Cerebrovasc Dis 2004; 17(suppl 1): 1-6 With neuroprotection Ischemic damage minimised Without neuroprotection Permanent ischemic damage
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Hinweis der Redaktion
Stroke is the third leading cause of death in the United States and the most common cause of adult disability. An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. The only currently approved stroke therapy, tissue plasminogen activator, is a thrombolytic that targets the thrombus within the blood vessel. Neuroprotective agents, another approach to stroke treatment, have generated as much interest as thrombolytic therapies. Using various mechanisms, neuroprotective agents attempt to save ischemic neurons in the brain from irreversible injury. Studies in animals indicate a period of at least 4 hours after onset of complete ischemia in which many potentially viable neurons exist in the ischemic penumbra. In humans, the ischemia may be less complete, and the time window may be longer, but human patients also tend to be older with comorbidities that may limit benefit. As many neuroprotective drugs reduce ischemic damage in animal models of stroke, this line of pharmaceutical research holds great promise. Many are searching for a safe agent that can limit ischemic damage in human stroke. One action of neuroprotective agents limits acute injury to neurons in the penumbra region or rim of the infarct after ischemia. Neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury. Returning blood contains leukocytes that may occlude small vessels and release toxic products.
Stroke is the third leading cause of death in the United States and the most common cause of adult disability. An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. The only currently approved stroke therapy, tissue plasminogen activator, is a thrombolytic that targets the thrombus within the blood vessel. Neuroprotective agents, another approach to stroke treatment, have generated as much interest as thrombolytic therapies. Using various mechanisms, neuroprotective agents attempt to save ischemic neurons in the brain from irreversible injury. Studies in animals indicate a period of at least 4 hours after onset of complete ischemia in which many potentially viable neurons exist in the ischemic penumbra. In humans, the ischemia may be less complete, and the time window may be longer, but human patients also tend to be older with comorbidities that may limit benefit. As many neuroprotective drugs reduce ischemic damage in animal models of stroke, this line of pharmaceutical research holds great promise. Many are searching for a safe agent that can limit ischemic damage in human stroke. One action of neuroprotective agents limits acute injury to neurons in the penumbra region or rim of the infarct after ischemia. Neurons in the penumbra are less likely to suffer irreversible injury at early time points than are neurons in the infarct core. Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow. Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury. Returning blood contains leukocytes that may occlude small vessels and release toxic products.
Free radicals generated during cerebral ischemia or reperfusion are thought to have a significant role in the development of brain injury 1 . The aim of neuroprotection in acute ischemic stroke is to preserve viable brain cells in the ischemic penumbra by interfering with the damaging events of the ischemic cascade 2 . References 1. Green AR, Ashwood A. Free radical trapping as a therapeutic approach to neuroprotection in stroke: experimental and clinical studies with NXY-059 and free radical scavengers. Curr Drug Targets CNS Neurol Disord 2005; 4: 109-118. 2 . Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999; 22: 391-397.
Limiting the area and impact of injury to neuronal cells in the ischemic penumbra may improve recovery from stroke 1 . Extensive research has increased the understanding of potential targets of neuroprotection during ischemia 2 . References 1. Fisher M. The ischemic penumbra: identification, evolution and treatment concepts. Cerebrovasc Dis 2004; 17 (suppl 1): 1-6. 2. Lo EH, Dalkara T, Moskowitz MA. Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 2003; 4: 399-415.
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