Article

NEUROPROTEKCYJNA ROLA ADENOZYNY

ABSTRACT Wstêp Ostatnie 25 lat dostarczy³o licznych dowodów na wa¿n¹ rolê adenozyny jako endogennego zwi¹z-ku neuroprotekcyjnego, zarówno w stosunku do uszkodzeñ niedokrwiennych, drgawkowych czy te¿ spowodowanych ekscytotoksycznooeci¹. W tych sta-nach patologicznych, przy wystêpuj¹cym deficycie energetycznym, dochodzi do nasilenia uwalniania pobudzaj¹cych aminokwasów a szczególnie gluta-minianu. Nastêpstwem tego jest gwa³towny wzrost pozakomórkowego poziomu adenozyny (od wartooeci nanomolarnych do mikro-i milimolarnych). Z kolei uwolniona adenozyna, dzia³aj¹c poprzez receptory adenozynowe A 1 hamuje uwalnianie glutaminianu, co mo¿e przyczyniaae siê do jej dzia³ania ochronne-go. Podobne, neuroprotekcyjne efekty stwierdzono równie¿ po podaniu inhibitorów enzymów, bior¹cych udzia³ w rozk³adzie (tj. kinazy i deaminazy adeno-zyny) oraz wychwycie zwrotnym adenozyny, bo-wiem zwiêkszaj¹ one pozakomórkowy poziom ade-nozyny w mózgu. Receptory adenozynowe A 2A wy-daj¹ siê odgrywaae wa¿n¹ rolê w przewlek³ych chorobach neurodegeneracyjnych, takich jak choro-ba Parkinsona czy Huntingtona. W ostatnich latach wykazano bowiem, ¿e selektywni antagonioeci tych receptorów dzia³aj¹ przeciwparkinsonowsko w zwie-rzêcych modelach tej choroby. Ponadto, zarówno blokada jak te¿ inaktywacja receptorów A 2A dzia³a neuroprotekcyjnie, zmniejszaj¹c stopieñ uszkodzeñ wywo³anych podaniem MPTP czy 6-hydroksydopa-miny. Fakt, ¿e antagonioeci receptorów A 2A dzia³aj¹ leczniczo zarówno objawowo jak i ochronnie w zwie-rzêcych modelach choroby Parkinsona sugeruje, ¿e zwi¹zki te mog³yby nie tylko poprawiaae zaburzenia motoryczne obserwowane w jej przebiegu ale te¿ spowalniaae rozwój tej choroby. Pierwsze próby kli-nicznego zastosowania s¹ dopiero w toku (zakoñ-czona II faza badañ klinicznych zwi¹zku KW6002) i jak na razie nie wiadomo, czy bêd¹ one rzeczywi-oecie tak obiecuj¹ce, jak wskazuj¹ na to badania na zwierzêtach.

0 Bookmarks
 · 
142 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pathophysiological role of the adenosine A3 receptor in the central nervous system is largely unknown. We have investigated the effects of the selective A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine, Cl-IB-MECA, in cells of the astroglial lineage (human astrocytoma ADF cells). A marked reorganization of the cytoskeleton, with appearance of stress fibers and numerous cell protrusions, was found following exposure of cells to low (nM) concentrations of Cl-IB-MECA. These "trophic" effects were accompanied by induction of the expression of Rho, a small GTP-binding protein, which was virtually absent in control cells, and by changes of the intracellular distribution of the antiapoptotic protein Bcl-XL, that, in agonist-exposed cells, became specifically associated to cell protrusions. This is the first demonstration that the intracellular organization of Bcl-XL can be modulated by the activation of a G-protein-coupled membrane receptor, such as the A3 adenosine receptor. Moreover, modulation of the astrocytic cytoskeleton by adenosine may have intriguing implications in both nervous system development and in the response of the brain to trauma and ischemia.
    Biochemical and Biophysical Research Communications 01/1998; 241(2):297-304. · 2.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Huntington's disease (HD) is an autosomal dominant neurological disorder characterized by progressive chorea, cognitive impairment and emotional disturbance. The disease usually occurs in midlife and symptoms progress inexorably to mental and physical incapacitation. It has been postulated that an excitotoxin is involved in the pathogenesis of HD. Schwarcz and colleagues have shown that quinolinic acid (QA) can produce axon-sparing lesions similar to those observed in HD. The lesions result in a depletion of neurotransmitters contained within striatal spiny neurones, for example gamma-aminobutyric acid (GABA), while dopamine is unaffected. Recently, we and others have demonstrated that in HD striatum there is a paradoxical 3-5-fold increase in both somatostatin and neuropeptide Y which is attributable to selective preservation of a subclass of striatal aspiny neurones in which these peptides are co-localized. In the present study we demonstrate that lesions due to quinolinic acid closely resemble those of HD as they result in marked depletions of both GABA and substance P, with selective sparing of somatostatin/neuropeptide Y neurones. Lesions produced by kainic acid (KA), ibotenic acid (IA) and N-methyl-D-aspartate (MeAsp) were unlike those produced by QA, as they affected all cell types without sparing somatostatin/neuropeptide Y neurones. These results suggest that QA or a similar compound could be responsible for neuronal degeneration in HD.
    Nature 01/1986; 321(6066):168-71. · 38.60 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 1. Quinolinic acid may be an important endogenous excitotoxin, but its concentrations in brain are low. We have therefore attempted to determine whether its neurotoxicity can be increased by the simultaneous presence of free radicals. 2. Quinolinic acid was injected into the hippocampus of anaesthetized rats at doses of 40 and 80 nmols which produced little neuronal loss, and 120 nmols which produced over 90% neuronal loss. 3. A mixture of xanthine and xanthine oxidase, a known source of free radical reactive oxygen species, also generated little damage alone, but killed over 80% of CA1 neurons when combined with 80 nmols of quinolinic acid. Similarly, the nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) potentiated the damage produced by quinolinic acid. 4. The glutamate antagonist 5,7-dichlorokynurenic acid prevented the damage produced by 120 nmols of quinolinic acid, but not that produced by quinolinic acid plus xanthine/xanthine oxidase, indicating that damage was not simply the result of free radical enhancement of NMDA receptor activation. 5. Three chemically dissimilar antagonists at adenosine A(2A) receptors prevented the damage caused by quinolinic acid and xanthine/xanthine oxidase or by quinolinic acid plus SNAP. 6. It is concluded that reactive oxygen species can potentiate the neurotoxicity of quinolinic acid. The site of interaction is probably distal to the NMDA receptor. Blockade of adenosine A(2A) receptors can protect against this combined damage, suggesting potential value in the prevention of brain damage.
    British Journal of Pharmacology 04/2002; 135(6):1435-42. · 5.07 Impact Factor

Full-text

Download
5 Downloads
Available from