Received for publication June 3, 2005.
Revised August 1, 2005.
Accepted for publication August 2, 2005.

Substance P, Neurokinins A and B, and Synthetic Tachykinin Peptides Protect Mesencephalic Dopaminergic Neurons in Culture via an Activity-Dependent Mechanism

Abstract

We evaluated the neuroprotective potential of tachykinin peptides using a model system in which mesencephalic dopaminergic (DA) neurons die spontaneously and selectively as they mature. The three native tachykinins, substance P (SP), neurokinin (NK) A and NKB afforded substantial protection against DA cell demise. The selective NK₁ receptor antagonist GR71251 was sufficient in itself to suppress the effect of SP whereas a co-treatment with GR71251 and the NK₃ receptor antagonist SB218795 was required to prevent the effects of both NKA and NKB. Consistent with these results, GR73632, a selective agonist of NK₁ receptors and [pro7]-NKB, a selective agonist of NK₃ receptors, conferred protection to DA neurons whereas GR64349, which activates specifically NK₂ receptors, did not. DA neurons rescued by tachykinins accumulated [³H]-DA efficiently which suggests that they were also totally functional. Neuroprotection by tachykinins was highly selective for DA neurons, rapidly reversed upon treatment withdrawal and reproduced by, but independent of glial cell line-derived neurotrophic factor. Survival promotion by tachykinins was abolished by blocking voltage-gated Na⁺ channels with tetrodotoxin or N-type voltage-gated Ca²⁺ channels with -conotoxin-MVIIA, which indicates that an increase in neuronal excitability was crucially involved in this effect. Together, these data further support the notion that the survival of mesencephalic DA neurons during development depends largely on excitatory inputs, which may be provided in part by tachykinins.

Key words: Dopamine, Neuropeptides, Tachykinin, Excitotoxicity, neurodegeneration

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