BCN Annual Report Mechanism of Neurodegeneration and Neuroprotection Neuroprotection against

							BCN Annual Report 1999 2000 2001                                         Mechanism of Neurodegeneration and Neuroprotection




                         4.13      Neuroprotection against brain damage in
                                   Alzheimer and stroke models
Oosterink B.J., Harkany T., Nyakas C., Korf J., Penke* B., Luiten P.G.M.

                                   *Dept. of Medical Chemistry, University of Szeged, Hungary

                                   Brain damage after ischemic stroke is thought to result from overstimulation by the neurotrans-
                                   mitter glutamate released from glutamate nerve terminals as a consequence of the lack of oxygen
                                   and glucose, and thus lack of energy after stroke. Such energy depletion causes a chronic state of
                                   depolarization of the nerve cell which eventually will lead to severe calcium overload and massive
                                   neuronal cell death. Most if not all drugs developed to combat brain damage after stroke were so far
                                   clinically unsuccessful. This prompted us to start new approaches based on the phenomenon to
                                   hyperpolarize nerve cells and this way to reverse the depolarization after stroke. Such an effect can
                                   be achieved by application of serotonin-1A receptor agonists like 8-OH-DPAT and repinotan. To test
                                   this hypothesis we initiated ischemic cell death by local infusions of the glutamate analog NMDA
                                   to cholinergic nerve cells after which we studied cell death and loss of function in a memory test. We
                                   then applied the serotonin1A agonists before and in a range of time periods after the start of the
                                   brain damage. As we expected the application of the drugs before the induction of brain damage
                                   strongly dimished cell death. More importantly, however, the serotonergic drugs also significantly
                                   reduced cell death when we applied the drugs between 6 to 48 hours after the onset of the neurode-
                                   generative process. This effect was established both by microscopic visualization of the lower degree
                                   of cell death and by the improved performance of the rats in the memory test. The fact that such
                                   compounds are effective such a long period after the initiation of the neuronal injury may be of
                                   great clinical importance since in most if not all cases treatment of stroke can only start several
                                   hours after occurrence of the stroke.

                                   Next to the NMDA stroke-associated cell damage particular interest is directed towards the mecha-
                                   nism through which amyloid-β peptides induce neuronal injury. Beta amyloid peptides are abnor-
                                   mal small proteins produced in the brains of Alzheimer patients, which are thought to be a major
                                   component in the neurodegenerative process in Alzheimer’s disease. Our experimental studies
                                   point to a glutamate mediated neurotoxic mechanism that is triggered by Aβ aggregates. We found
                                   that injections of Aβ in the brains of experimental animals like rat and mouse leads to cell death
                                   that is mediated by glutamate overstimulation. The excess glutamate is a consequence of the fact
                                   that Aβ inhibits glial cells to absorp the released glutamate from neuronal endings. This way a
                                   microenvironment is created in which the Aβ surrounding neuronal structures are chronically
                                   overstimulated eventually leading to cell death. This certainly will not be the only neurodegenera-
                                   tive mechanism, but in concert with other risk factors like a diminished blood supply to the brain
                                   and neuroinflammaotory mechanisms this excitotoxic process can result in the widespread pathol-
                                   ogy that is characteristic for Alzheimre’s dieseas. Recent studies are aimed at neuroprotective strate-
                                   gies to combat Aβ toxicity by anti-amyloid peptides and so-called β-sheet breakers.

                                   Several other risk factors can determine the progress of the degeneration progress both is ischemic
                                   stroke and in Alzheimer’s disease. One of the factors that we study is the impact of the adrenal stress
                                   hormone cortisol or corticosterone. This hormone level is enhanced in Alzheimer and Parkinson
                                   patients and is acutely elevated after stroke. Both lack of corticosterone after removal of the adrenal
                                   gland and excessively high corticosterone levels as in chronic stress significantly enhanced the
                                   impact of NMDA and β-A induced brain damage (figure 12). However, moderately elevated concen-
                                   trations of corticosterone suppress the damaging effects of glutamate and can be interpreted as
                                   being neuroprotective.
BCN Annual Report 1999 2000 2001                                                                              Mechanism of Neurodegeneration and Neuroprotection




Figure 12 > Effect of different plasma   (B)
                                                                                           30
corticosterone concentrations on the                                              30
loss of cholinergic projection fibers




                                         Percentage of AChE positive fibre loss
in the somatosensory cortex follow-                                                        15
                                                                                  25
ing unilateral injections of the toxic
Alzheimer protein Aβ in the cholin-
                                                                                            0
ergic magnocellular nucleus basalis.                                              20         0   325    650
Acetylcholinesterase (AChE)-positive
fibers loss was expressed as the per-                                             15
centage difference between AChE
fiber density in the lesioned and
contralateral sides of the brain. (B)                                             10

Scatter-plot of the relationship of
corticosterone concentrations and                                                  5
the percentage of fiber loss. The
horizontal dashed line indicates the
                                                                                   0
level of Aβ-induced neuronal injury                                                    0          200          400         600
in adrenally intact animals.                                                                      Corticosterone (nM)