
KP-10 (Kisspeptin-10): Studies on Neuroprotection, Gonadotropin Regulation, and Emotional Processing
Initial characterization of KISS1 positioned it as a gene that has been observed acting as a metastasis suppressor in mammalian research models, particularly in the contexts of malignant melanoma and breast tissue carcinoma.[1] Its expression profile and tissue-specific activity have since led to growing interest in the neuroendocrine impacts of its peptide products. Kp-10 has been proposed to interact with central regulatory systems involved in reproduction, particularly through its hypothetical impacts on the hypothalamic-pituitary axis.
The KISS1 receptor (KISS1R), also referred to as GPR54, is a G-protein-coupled receptor that binds Kp-10 and other Kisspeptin fragments. This interaction has been proposed as a key upstream regulator of hypothalamic GnRH release, with implications for the modulation of puberty onset and fertility pathways specific to mammals.[3]
Contents:
- Mechanisms of Action
- Scientific and Research Studies
- KP-10 (Kisspeptin-10) and the Gonadal Axis
- KP-10 (Kisspeptin-10) and Neuroprotection
- Metabolic Dysregulation in Deficient Models
- KP-10 (Kisspeptin-10)and Caloric Intake Regulation
- KP-10 (Kisspeptin-10) and Behavioral Patterns and Emotional Modulation
- KP-10 (Kisspeptin-10) and Reproductive Hormone Secretion
- References
Mechanisms of Action
Research suggests that KP-10 may act as an endogenous ligand for GPR54, and this receptor-ligand interaction may initiate intracellular signaling cascades in hypothalamic neurons. These pathways are hypothesized to lead to calcium mobilization, arachidonic acid release, and phosphorylation of extracellular signal-regulated kinases, which may contribute to the depolarization of both Kisspeptin and GnRH neurons.[4]
Activation of GnRH neurons is central to the release of gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—from the anterior pituitary. These hormones are considered to regulate mammalian gonad function, and the synthesis of reproductive hormones as observed in murine models in laboratory settings. Studies suggest that deficiencies in this axis, most often observed in conditions such as hypogonadotropic hypogonadism, may be linked to impaired Kisspeptin signaling, highlighting a possible research interest in peptides like KP-10.[3.]
Experimental findings in less-fertile murine research models suggest that the exogenous introduction of Kisspeptin analogs may stimulate endogenous gonadotropin release, possibly through GnRH-dependent mechanisms. Additionally, sustained exposure or elevated concentrations of KP-10 may be associated with a desensitization response. This type of exposure may suppress further activity along the hypothalamic-pituitary-gonadal (HPG) axis, although this remains under investigation.
The physiological outcomes of KP-10 interaction with GPR54 may vary based on concentration, receptor sensitivity, and developmental stage. Ongoing research continues to explore its regulatory role and expression patterns in both central and peripheral tissues.
Scientific Research and Studies
KP-10 (Kisspeptin-10) and the Gonadal Axis
Experimental investigations into delayed reproductive maturation in mammals have included assessments of KP-10 as a potential modulator of the hypothalamic-pituitary-gonadal (HPG) axis. In one such study, researchers investigated whether exposure to KP-10 in preclinical laboratory settings with delayed developmental trajectories might impact luteinizing hormone (LH) secretion dynamics, considered to be a key marker of gonadotropic activation.
The research design involved the introduction of either KP-10 or a reference concentration of gonadotropin-releasing hormone (GnRH) to randomized cohorts of research models. Following an acute phase of hormonal monitoring, all test subjects were subsequently exposed to GnRH over a six-day observation period, allowing for comparative analysis of LH responses.
Data analysis revealed that approximately 47% of the KP-10-exposed group indicated an elevation in LH levels following exposure, suggesting a potential sensitization or activation of GnRH neurons. An additional 6% exhibited a partial or intermediate hormonal response, while the remaining research models showed no measurable change in LH secretion under the experimental conditions.
These findings contribute to ongoing efforts to elucidate the role of Kisspeptin peptides in developmental endocrinology, particularly in research models characterized by disrupted or delayed activation of the HPG axis. Further studies are warranted to clarify receptor sensitivity, neuroendocrine timing, and the interplay between the peptide GnRH axis across different developmental stages.
KP-10 (Kisspeptin-10) and Neuroprotection
Emerging data suggests that the deposition of amyloidogenic proteins, including amyloid-beta (Aβ) and alpha-synuclein (α-syn), may contribute to the progressive deterioration of cholinergic neurons within the central nervous system. These protein aggregates are widely regarded as playing a significant role in the pathogenesis of several neurodegenerative disorders due to their ability to disrupt cellular integrity and synaptic transmission. Investigations into the bioactivity of KP-10 (KP-10) have proposed that this decapeptide may interact directly with extracellular Aβ, potentially mitigating its pathological actions through competitive binding or conformational interference.[6]
Experimental findings have indicated that KP-10 may exhibit a capacity to neutralize or suppress the neurotoxicity associated with Aβ, prion protein (PrP), and islet amyloid polypeptide (IAPP), and that this activity may occur independently of GPR54 or NPFF receptor antagonism. Such receptor-independent actions suggest a physicochemical mode of interaction that does not require canonical signal transduction through known Kisspeptin-binding receptors.
Given the sequence and structural homology between the non-amyloid-β component (NAC) region of α-syn and the C-terminal region of Aβ, researchers have hypothesized that KP-10 may similarly exhibit antagonistic activity against α-syn aggregation. In vitro studies examining cholinergic neuronal models have hypothesized that low nanomolar concentrations of KP-10 are associated with a measurable attenuation of α-syn-induced cytotoxicity, including that mediated by the pathogenic E46K mutation.
Conversely, exposure to supraphysiological levels of KP-10 has been correlated with better-supported cellular detox, suggesting a concentration-dependent biphasic impact.[7] Molecular dynamics simulations provided further support for this proposed interaction, indicating the formation of stable, energetically favorable complexes between KP-10 and the C-terminal residues of α-syn, which may interfere with oligomerization or fibril formation.
To elucidate the mechanistic relevance of GPR54 signaling in these impacts, cholinergic SH-SY5Y cells overexpressing either wild-type or mutant α-syn were examined following exposure to KP-10 in the presence and absence of the GPR54 antagonist KP-234. Flow cytometric analysis and immunocytochemical evaluation revealed a reduction in apoptotic markers and mitochondrial damage following KP-10 exposure, regardless of whether receptor blockade was present. This observation suggests that KP-10’s neuroprotective impacts may be mediated via receptor-independent mechanisms, possibly through direct protein-protein interactions or membrane-associated pathways.
Further analysis revealed that the introduction of KP-10 led to a marked reduction in α-syn and choline acetyltransferase (ChAT) expression in neurons expressing both wild-type and mutant α-syn constructs. This finding aligns with the hypothesis that KP-10 may interfere with the stability or intracellular accumulation of aggregation-prone proteins, thereby preserving neuronal phenotype and function under proteotoxic stress.
Metabolic Dysregulation in Deficient Models
Experimental assessments of KP-10 deficiency have highlighted marked sex-specific alterations in metabolic function. In a comparative murine study, the energetic and glycoregulatory consequences of disrupted KP-10 signaling were evaluated in both male and female murine models.[8] Female murine models with impaired KP-10 systems exhibited significant support for the growth in mass and the development of more pronounced glucose intolerance. Despite a reduction in caloric intake compared to control females, the KP-10-deficient group exhibited better-supported adiposity, reduced locomotor activity, and mitigated respiratory exchange ratios, indicating impaired metabolic flexibility and energy utilization.
Conversely, male murine models with comparable disruptions in KP-10 signaling displayed no statistically significant differences in overall mass or glucose tolerance when compared to male murine models in the control group. These findings suggest a potentially sex-dependent chromosomal role of KP-10 in modulating metabolic pathways, with the physiology of female murine models appearing particularly sensitive to alterations in KP-10-mediated signaling.
KP-10 (Kisspeptin-10) and Caloric Intake Regulation
Kisspeptin-10 (KP-10) has been identified in multiple brain regions of murine models, including the hippocampus, cerebellum, posterior hypothalamus, and septum. Its notable distribution within hypothalamic nuclei implicated in energy homeostasis, particularly the arcuate nucleus (Arc), has led to growing interest in its potential modulatory role in behavioral patterns that involve caloric intake.
To further understand this, a study was conducted to evaluate the impacts of KP-10 exposure on caloric intake in adult male murine models aged 6-8 weeks. The murine models were maintained under standard housing conditions with ad libitum access to a regular murine diet and water.[9]
Experimental procedures involved the introduction of various concentrations of KP-10 or placebo to two groups: overnight-fasted and fed murine models. In fasted murine models, KP-10 introduction was associated with a suppression of caloric intake during the initial 3- to 12-hour post-observation period. Interestingly, this anorexigenic impact appeared transient. As caloric intake was ramped up by supervising researchers during the subsequent 12- to 16-hour period, the results showed a cumulative intake comparable to that of the research models in the control group. A detailed behavioral analysis revealed that KP-10 exposure led to a reduction in frequency and total duration of time spent consuming calories, accompanied by a concomitant increase in inter-consumption intervals. However, the amount and rate of caloric intake did not appear to differ significantly between the KP-10 and control groups.
To further elucidate the underlying mechanisms, subsequent studies investigated the potential central regulatory impacts of KP-10 on hypothalamic pathways involved in appetite control. In particular, the impacts of KP-10 exposure on gene expression and neurotransmitter dynamics were assessed in Hypo-E22 hypothalamic cell lines. Findings indicated that KP-10 may have exerted a transcriptional impact by upregulating neuropeptide Y (NPY), a potent orexigenic peptide, and concurrently downregulating brain-derived neurotrophic factor (BDNF), which is generally associated with suppression of hunger hormone signaling.
In addition to transcriptional modulation, KP-10 appeared to alter monoaminergic neurotransmission within hypothalamic cells. Exposure to the peptide resulted in reduced intracellular concentrations of dopamine and serotonin (5-hydroxytryptamine; 5-HT), while norepinephrine levels remained relatively unchanged. These alterations were accompanied by support of the respective metabolite-to-neurotransmitter ratios – dihydroxyphenylacetic acid (DOPAC)/dopamine and 5-hydroxyindoleacetic acid (5-HIAA)/serotonin – suggesting better-supported turnover of dopamine and serotonin following KP-10 introduction.
As per researchers:
“this study shows in mice that KP-10 acts centrally to reduce the light phase food intake response to an overnight fast with a delayed onset, whereas the nocturnal food intake is not altered. The reduction in feeding after a fast is achieved through mitigation in meal frequency and is associated with prolonged inter-meal intervals. Such changes in microstructure pattern of feeding are indicative of a stimulatory impact on satiety, which was not related to alterations in gastric emptying of a meal.”
The combination of elevated NPY expression, suppressed BDNF transcription, and diminished serotonergic and dopaminergic signaling suggests a potential role for KP-10 in modulating hypothalamic circuits that regulate behavioral patterns related to caloric intake and energy balance.[10]
KP-10 (Kisspeptin-10) and Behavioral Patterns and Emotional Modulation
A recent investigation aimed to evaluate the impact of KP-10 on limbic system activity, a brain region implicated in behavioral regulation.[11] Utilizing a combination of neuroimaging modalities and standardized psychometric assessments, the study examined central responses to exogenous KP-10 introduction.
Data obtained from these assessments suggested that KP-10 exposure was associated with better-supported activation within limbic structures, “specifically in response to sexual and couple-bonding stimuli.” Additionally, as per the researchers, “Kisspeptin’s enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, Kisspeptin [exposure] attenuated negative [behavioral patterns].”
These observations suggest a potential neuromodulatory role for KP-10 in neurological processing within the central nervous system, particularly in behavioral regulation.
KP-10 (Kisspeptin-10) and Reproductive Hormone Secretion
Another study was conducted to characterize the impacts of KP-10 on gonadotropin release in both male and female murine models.[11] Following peptide exposure, research models appeared to exhibit a marked elevation in circulating levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), supporting the hypothesized stimulatory role of KP-10 on the hypothalamic–pituitary–gonadal (HPG) axis.
In contrast, baseline levels of FSH and LH in female murine models remained largely unimpacted across the general menstrual cycle. Notably, however, during the preovulatory phase, when gonadotropin sensitivity is heightened, the introduction of KP-10 was correlated with significant support of FSH and LH levels. These findings suggest a phase-dependent modulatory impact of KP-10 on reproductive endocrine activity, potentially mediated by interactions with upstream hypothalamic regulators.
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References:
- KISS1 KiSS-1 metastasis suppressor [Homo sapiens (humans)]. https://www.ncbi.nlm.nih.gov/gene/3814
- Mead, E. J., Maguire, J. J., Kuc, R. E., & Davenport, A. P. (2007). Kisspeptin: a multifunctional peptide system with a role in reproduction, cancer, and the cardiovascular system. British journal of pharmacology, 151(8), 1143–1153. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189831/
- Hussain, Mehboob A et al. “There is Kisspeptin – And Then There is Kisspeptin.” Trends in endocrinology and metabolism: TEM vol. 26,10 (2015): 564-572. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4587393/
- Rønnekleiv, O. K., & Kelly, M. J. (2013). Kisspeptin excitation of GnRH neurons. Advances in experimental medicine and biology, 784, 113–131. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019505/
- Kristen P. Tolson et.al, Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. The Journal of Clinical Investigation. Published June 17, 2014. https://www.jci.org/articles/view/71075
- Milton NG, Chilumuri A, Rocha-Ferreira E, Nercessian AN, Ashioti M. Kisspeptin prevention of amyloid-β peptide neurotoxicity in vitro. ACS Chem Neurosci. 2012 Sep 19;3(9):706-19. doi: 10.1021/cn300045d. Epub 2012 May 30. PMID: 23019497; PMCID: PMC3447396. https://pmc.ncbi.nlm.nih.gov/articles/PMC3447396/
- Simon, C., Soga, T., Ahemad, N., Bhuvanendran, S., & Parhar, I. (2022). Kisspeptin-10 (KP-10) Rescues Cholinergic Differentiated SHSY-5Y Cells from α-Synuclein-Induced Toxicity In Vitro. International journal of molecular sciences, 23(9), 5193. https://doi.org/10.3390/ijms23095193
- Kristen P. Tolson et.al, Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. The Journal of Clinical Investigation. Published June 17, 2014. https://www.jci.org/articles/view/71075
- Stengel, A., Wang, L., Goebel-Stengel, M., & Taché, Y. (2011). Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport, 22(5), 253–257. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3063509/
- Orlando G, Leone S, Ferrante C, Chiavaroli A, Mollica A, Stefanucci A, Macedonio G, Dimmito MP, Leporini L, Menghini L, Brunetti L, Recinella L. Impacts of Kisspeptin-10 on Hypothalamic Neuropeptides and Neurotransmitters Involved in Appetite Control. Molecules. 2018 Nov 24;23(12):3071. doi: 10.3390/molecules23123071. PMID: 30477219; PMCID: PMC6321454. https://pmc.ncbi.nlm.nih.gov/articles/PMC6321454/
- Comninos, A. N., Wall, M. B., Demetriou, L., Shah, A. J., Clarke, S. A., Narayanaswamy, S., Nesbitt, A., Izzi-Engbeaya, C., Prague, J. K., Abbara, A., Ratnasabapathy, R., Salem, V., Nijher, G. M., Jayasena, C. N., Tanner, M., Bassett, P., Mehta, A., Rabiner, E. A., Hönigsperger, C., Silva, M. R., Dhillo, W. S. (2017). Kisspeptin modulates sexual and emotional brain processing in humans. The Journal of clinical investigation, 127(2), 709–719. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272173/