Page 22 - 71_02

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

microinjection of ATP analogues into the prepiriform cortex induces

generalised motor seizures. P2X2, P2X4 and P2X6 receptors are
expressed in the prepiriform cortex, suggesting that a P2X receptor

antagonist may have potential as a neuroleptic agent. The

hippocampus of chronic epileptic rats shows abnormal responses to

ATP associated with increased expression of P2X7 receptors; it has
been suggested that purinergic receptors (perhaps on microglia) may

participate in the pathophysiology of temporal lobe epilepsy.

In nervous tissue, trophic factors ensure neuronal viability
and regeneration. Neuronal injury releases fibroblast growth
factor, epidermal growth factor and platelet-derived growth factor.
In combination with these growth factors, ATP can stimulate
astrocyte proliferation, contributing to the process of reactive
astrogliosis and to hypertrophic/hyperplastic responses. P2Y receptor
antagonists have been proposed as potential neuroprotective agents
in the cortex, hippocampus and cerebellum, by modulation of kainate
and AMPA-induced currents, excessive activation of glutamate
receptor systems being implicated in neuronal cell death associated
with stroke, epileptic seizures and neurodegenerative diseases such
as Alzheimers, Parkinson’s, Huntington’s and amyotrophic lateral
scoliosis (ALS). P2 receptors have been claimed to mediate
neuroprotective effects in the cerebellum and the possibility of
the therapeutic use of P2 receptor agonists as neuroprotective
agents raised. Upregulation of P2X1 and P2X2 receptors after
cerebellar lesions has been reported. Purine derivatives are in
clinical trials as memory-enhancing agents in Alzheimers disease;
two of these, propentofylline and AIT-082 appear to act as trophic
effectors, increasing the production of neurotrophic factors in brain
and spinal cord. It has been reported that aluminium can produce
Alzheimer-like symptoms and a mechanism has been proposed
whereby the aluminium binds to ATP to act on P2 purinoceptors
leading to formation of amyloid fibrils. Adenosine is claimed to have
a protective effect in a rat model of Parkinson’s disease, perhaps by
upregulating antioxidant states and reducing dopamine loss.
Blockade of A2A (P1) receptors antagonises parkinsonian tremor in
the rat tacrine model by actions on specific striated regions.
Increased A2A receptors in the brain of Parkinson’s disease patients
with dyskinesias has been described recently, which reinforces the

302