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 NK 1 receptor antagonist [D-Pro9,[spiro-␥-lactam] Leu10,Trp11]substance P (GR71251) was sufficient in itself to suppress the effect of SP, whereas a cotreatment with GR71251 and the NK 3 receptor antagonist (R)-N-[␣-(methoxycarbonyl)benzyl]-2-phenylquinoline-4-carboxamide (SB218795) was required to prevent the effects of both NKA and NKB. Consistent with these results, D-Ala-[LPro9,Me-Leu8]substance P(7-11) (GR73632), a selective agonist of NK 1 receptors and [pro7]-NKB, a selective agonist of NK 3 receptors, conferred protection to DA neurons, whereas (Lys3, Gly8-R-␥-lactam-Leu9)neurokinin A(3-10) (GR64349), which activates specifically NK 2 receptors, did not. DA neurons rescued by tachykinins accumulated [ 3 H]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 ϩ channels with tetrodotoxin or N-type voltagegated Ca 2ϩ 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.

Modulation of lymphatic muscle contractility by the neuropeptide substance P

“…Furthermore, the effects of SP on rat mesenteric lymphatics are probably mediated by a combination of NK receptors (NK 1 / NK 2 ), as has been recently shown for human visceral smooth muscle where a strong inotropic response is also observed (30). Alternatively, if the lymphatic pacemaker is controlled by interstitial cells of Cajal-like neurons (32,33), it is possible that NK 3 receptors may be involved, since this receptor is known to be associated with neurons (8,40). Thus the specific SP receptors mediating positive inotropic and chronotropy in rat mesenteric lymphatics remain uncertain, and systematic experiments using more selective antagonists for specific NK receptor subtypes will be required to resolve this issue.…”

Dopamine and Aging: Intersecting Facets

“…channels. Tachykinins are protective against excitotoxicity, b-amyloid and growth factor withdrawal [181].…”

Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels

“…Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in SNc with major symptoms including resting tremor, akynesia and disturbance of posture 4 . One practical approach for alleviation of PD symptoms is to enhance the excitability of surviving dopaminergic neurons in SNc where the neuronal activity can be modulated by a variety of neurotransmitters, endogenous hormones and peptides 5,6 .…”