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GEOFFREY BURNSTOCK AN. R. ACAD. NAC. FARM.

striking changes in proliferation and morphology of astrocytes and
microglia. Some of the responses to ATP released during brain injury
are neuroprotective, but in some cases ATP contributes to the
pathophysiology initiated after trauma. It has been claimed that P2Y2
receptors activate neuroprotective mechanisms in astrocytic cells. In
contrast, experimental infusion of ATP into nucleus accumbens or
cerebral hemisphere of rats suggests that purines might be a signal
for induction of malignant brain tumours. Multiple P2X and P2Y
receptor types are expressed by astrocytes, oligodendrocytes and
microglia. P2Y receptors mediate reactive astrogliosis via induction
of Cox-2 and P2Y receptor antagonists might counteract excessive
Cox-2 activation in both acute and chronic neurological disease. P2
receptors also mediate regulation of Cox-2 in microglia. IL-1ß-
induced astrocyte activation is regulated by purinergic signalling;
this is compatible with the hypothesis that nucleotides released under
inflammatory conditions activate autocrine or paracrine signalling
pathways that modulate inflammation. ATP can activate P2X7
receptors in astrocytes to release glutamate, GABA and ATP, which
regulate the excitability of neurons. ATP release during neuronal
excitation or injury can enhance the inflammatory effects of
cytokines and prostaglandin E2 in astrocytes and may contribute to
chronic inflammation seen in Alzheimer’s disease. Astrocytic gap
junctions are involved in the neuroprotective process, in particular
to protect neurons from oxidative stress and glutamate toxicity.

Microglia, immune cells of the CNS, are also activated by purines
and pyrimidines to release inflammatory cytokines such as
interleukins 1ß and 6 and tumour necrosis factor (TNF-a); activated
microglia can also act as scavenger cells that induce apoptosis in
damaged neurons by releasing toxic factors, including NO. Thus,
while microglia may play an important role against infection in the
CNS, overstimulation of this immune reaction may accelerate the
neuronal damage caused by ischaemia, trauma or neurodegenerative
diseases such as Alzheimer’s and Parkinson’s disease, HIV,
encephalopathy, multiple sclerosis and amyotrophic lateral scoliosis
(ALS), which exhibit microglial proliferation and activation (25).
These authors showed that ATP inhibits cytokine release from
lipopolysaccharide-activated microglia via P2Y receptors and
suggested that P2Y agonists may be a potential treatment for toxic

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