Diadenosine tetraphosphate protects sympathetic terminals from 6-hydroxydopamine-induced degeneration in the eye.
OBJECTIVE
To examine diadenosine tetraphosphate (Ap(4)A) for its ability to protect the eye from neurodegeneration induced by subconjunctival application of 6-hydroxydopamine (6-OHDA).


METHODS
Intraocular neurodegeneration of anterior structures was induced by subconjunctival injections of 6-OHDA. Animals were pre-treated with topical corneal applications of Ap(4)A or saline.


RESULTS
6-OHDA caused miosis, abnormal pupillary light reflexes, a precipitous drop in intraocular pressure and loss of VMAT2-labelled (vesicle monoamine transporter-2, a marker for sympathetic neurones) intraocular neurones. Pre-treatment with Ap(4)A prevented all of these changes from being induced by 6-OHDA, demonstrably preserving the sympathetic innervation of the ciliary processes. This neuroprotective action of Ap(4)A was not shared with the related compounds adenosine, ATP or diadenosine pentaphosphate. P2-receptor antagonists showed that the effects of Ap(4)A were mediated via a P2-receptor.


CONCLUSIONS
Ap4A is a natural component of tears and aqueous humour, and its neuroprotective effect indicates that one of its physiological roles is to maintain neurones within the eye. Ap(4)A can prevent the degeneration of intraocular nerves, and it is suggested that this compound may provide the basis for a therapeutic intervention aimed at preventing or ameliorating the development of glaucoma associated with neurodegenerative diseases. Furthermore, subconjunctival application of 6-OHDA provides a useful model for studying diseases that cause ocular sympathetic dysautonomia.
Hoyle
C H V
CH
Dep. Bioquímica, Escuela Universitaria de Optica, Universidad Complutense de Madrid, Madrid, Spain.
Pintor
J J
JJ
D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D005123:Eye / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016627:Oxidopamine / Q000633:toxicity*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D013666:Tears / Q000737:chemistry; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D018663:Adrenergic Agents; D015226:Dinucleoside Phosphates; D018696:Neuroprotective Agents; D010975:Platelet Aggregation Inhibitors; D050493:Vesicular Monoamine Transport Proteins; C020733:diadenosine tetraphosphate; D016627:Oxidopamine