Secondary Neuropathology after Experimental Stroke With Special Emphasis on Calcium , Amyloid-β and Inflammation

One out of every three people will suffer either a stroke or develop Alzheimer’s disease (AD). In a world with continuous increase of life-expectancy the burden to healthcare system caused by these two neurological disorders will increase dramatically. It has become apparent that these two diseases share common pathological features, and this knowledge can be used to our advantage in finding new treatments. Focal cerebral ischemia in rodents is followed by delayed secondary pathology in the thalamus and this involves amyloid-β (Aβ) and calcium aggregation. This thesis has been done to further advance our understanding of the mechanisms behind this secondary pathology after cerebral ischemia and whether this pathology could be modified by the nonsteroidal anti-inflammatory drug ibuprofen (study I), the non-selective calcium channel inhibitor, bepridil (II and IV) and the reverse Na+/Ca2+ exchanger inhibitor, KB-R7943 (III). In study II, bepridil treatment after middle cerebral artery occlusion decreased the amounts of Aβ40 and Aβ42 as well as calcium levels in the ipsilateral thalamus in rats. The sensorimotor impairment was improved in bepridil treated MCAO animals. The data indicate that bepridil treatment prevents or modifies secondary pathology in the thalamus improving functional outcome. In study IV, transgenic AD mice were treated with bepridil after photothrombotic cortical lesion. There appeared to be less pronounced primary and secondary pathology in AD mice after ischemic cortical injury. It may be that the underlying AD pathology in the transgenic animals exerted a protective effect against cortical ischemic damage. The calcium pathology in the thalamus was effectively prevented by bepridil treatment. In study V, common marmosets subjected to transient middle cerebral artery occlusion were followed for forty-five days. The histological evaluation conducted after the follow-up did not show Aβ or calcium aggregates in the thalamus similar to those found in rodents. The data from studies I and III suggest that chronic ibuprofen or KB-R7943 treatment in rats does not improve behavioral outcome nor prevent secondary pathology in the thalamus after experimental focal ischemia. Secondary pathology after stroke is an attractive drug target since it has an extended therapeutic time window. Bepridil seems to alleviate the secondary pathology via a noninflammatory pathway and without interfering with amyloid precursor protein or Aβ cleavage and clearance. Data from these rodent studies indicates that calcium plays a more pivotal role than Aβ in the secondary pathological changes in the thalamus. The results from non-human primates after cerebral ischemia, however, show a complete lack of secondary pathology indicating that this may be a rodent specific phenomenon, which is likely to complicate translation of the data from rodents to humans. National Library of Medicine Classification: WL 356, QV 276, WD 205.5. A6, QZ 150 Medical Subject Headings: Stroke/pathology; Brain Ischemia; Infarction, Middle Cerebral Artery; Thalamus; Calcium; Calcium Channel Blockers; Amyloid; Amyloid beta-Peptides; Inflammation; Ibuprofen; Bepridil; Sodium-Calcium Exchanger/antagonists & inhibitors; Behavior; Disease Models, Animal