Recent studies have suggested that the kisspeptin (KP) and kissorphin (KSO) peptides have neuroprotective actions against the Alzheimer’s amyloid-β (Aβ) peptide. Overexpression of the human KiSS-1 gene that codes for KP and KSO peptides in SH-SY5Y neurons has also been shown to inhibit Aβ neurotoxicity. The in vivo actions of KP include activation of neuroendocrine and neurotransmitter systems. The present study used antagonists of KP, neuropeptide FF (NPFF), opioids, oxytocin, estrogen, adrenergic, cholinergic, dopaminergic, serotonergic, and γ-aminobutyric acid (GABA) receptors plus inhibitors of catalase, cyclooxygenase, nitric oxide synthase, and the mitogen activated protein kinase cascade to characterize the KiSS-1 gene overexpression neuroprotection against Aβ cell model. The results showed that KiSS-1 overexpression is neuroprotective against Aβ and the action appears to involve the KP or KSO peptide products of KiSS-1 processing. The mechanism of neuroprotection does not involve the activation of the KP or NPFF receptors. Opioids play a role in the toxicity of Aβ in the KiSS-1 overexpression system and opioid antagonists naloxone or naltrexone inhibited Aβ toxicity. The mechanism of KiSS-1 overexpression induced protection against Aβ appears to have an oxytocin plus a cyclooxygenase dependent component, with the oxytocin antagonist atosiban and the cyclooxygenase inhibitor SC-560 both enhancing the toxicity of Aβ. 1. Introduction Recent studies have suggested that the kisspeptin (KP) and kissorphin (KSO) peptide derivatives of the metastasis-suppressor KiSS-1 gene may have neuroprotective actions against the Alzheimer’s amyloid-β (Aβ) peptide [1]. The studies have also suggested that stable overexpression of the KiSS-1 gene in SH-SY5Y neurons creates a cell line that is resistant to the neurotoxicity of Aβ [1]. The primary role of KP peptides is as a regulator of hypothalamic-pituitary-gonadal- (HPG-) axis via stimulation of gonadotrophin-releasing hormone (GnRH) release [2]. The KP peptides are ligands for the GPR-54 receptor [3–7] and the neuropeptide FF (NPFF) receptors, NPFFR1 (GPR-147) and NPFFR2 (GPR-74) [3, 4, 6–9]. The KSO peptides have been suggested to be ligands for the NPFF receptors but not the GPR-54 receptor [10]. Both KP and KSO peptides are protective against the Aβ peptide in vitro [1]. However, the neuroprotective actions of KP and KSO peptides have been suggested not to be mediated via actions on GPR-54 or NPFF receptors [1]. Fibrillar Aβ peptides stimulate the release of KP peptides [1, 11] and KP has been suggested to
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