Tachykinins protect cholinergic neurons from quinolinic acid excitotoxicity in striatal cultures

The neuroprotective effect of tachykinins against excitotoxic death of cholinergic neurons was studied in rat striatal cell cultures. Quinolinic acid (QUIN) and kainic acid (KA) produced a dose dependent decrease in choline acetyltransferase activity, but KA was more potent. Our results show that substance P (SP) totally reversed the toxicity induced by 125 microM QUIN but not by 40 microM KA. This effect was also observed using protease inhibitors or a SP-analog resistant to degradation, [Sar9]-Substance P. The survival of neuron specific enolase- and acetylcholinesterase (AChE)-positive cells after treatment with QUIN alone or in the presence of SP was also examined. We observed that, while a decrease in total cell number produced by QUIN was not prevented by SP treatment, AChE-positive cells were rescued from the toxic damage. To characterize the SP protective effect we used more selective agonists of the three classes of neurokinin (NK) receptors. [Sar9, Met(O2)11]-Substance P (NK1 receptor agonist), [Nle10]-Neurokinin A (NK2 receptor agonist) or [Me-Phe7]-Neurokinin B (NK3 receptor agonist) were all able to block the toxic effect of QUIN on cholinergic activity. These results show that tachykinins provide an important protective support for striatal neurons, suggesting a possible therapeutical benefit in neurodegenerative disorders affecting cholinergic neurons.