Constant romantic feelings and experiences can protect against neurodegeneration: Potential role of oxytocin-induced nerve growth factor/protein kinase B/Cyclic response element-binding protein and nerve growth factor/protein kinase B/Phospholipase C-Gamma signaling pathways

Mina Gholami; Enzo Emanuele; Majid Motaghinejad

doi:10.4103/bbrj.bbrj_28_23

REVIEW ARTICLE

Year : 2023 | Volume : 7 | Issue : 1 | Page : 24-31

Constant romantic feelings and experiences can protect against neurodegeneration: Potential role of oxytocin-induced nerve growth factor/protein kinase B/Cyclic response element-binding protein and nerve growth factor/protein kinase B/Phospholipase C-Gamma signaling pathways

Mina Gholami¹, Enzo Emanuele², Majid Motaghinejad¹
¹ Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
² 2E Science, Robbio (PV), Italy

Date of Submission	18-Nov-2022
Date of Decision	06-Feb-2023
Date of Acceptance	20-Feb-2023
Date of Web Publication	14-Mar-2023

Correspondence Address:
Majid Motaghinejad
Masih Daneshvari Hospital, Darabad Avenue, Shahid Bahonar Roundabout, Tehran
Iran

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_28_23

Abstract

Neurodegeneration – defined as a progressive cell loss in specific neuronal populations – has devastating clinical consequences with significant societal and economic implications. Although effective preventive measures are still lacking, features of positive mental health and emotional resilience have the potential to reduce the risk of neurodegenerative diseases (NDDs). Romantic experiences – which are characterized by intense emotional intimacy – have complex biological underpinnings including an increased production and release of oxytocin and nerve growth factor (NGF). Because both oxytocin and NGF can protect against neurodegeneration, we propose our hypothesis that being constantly engaged in romantic feelings and experiences may delay or even prevent the onset of NDDs. We also propose that this could occur at the molecular level through the NGF/protein kinase B (Akt)/cyclic-adenosine monophosphate response element-binding protein and NGF/Akt/phospholipase C-gamma (PLC-γ) signaling pathways. In this article, we describe this conceptual framework and delineate potential avenues for future research in the field.

Keywords: Nerve growth factor, nerve growth factor/protein kinase B/cyclic response element-binding protein, nerve growth factor/protein kinase B/phospholipase C-gamma, oxytocin, romantic life

How to cite this article:
Gholami M, Emanuele E, Motaghinejad M. Constant romantic feelings and experiences can protect against neurodegeneration: Potential role of oxytocin-induced nerve growth factor/protein kinase B/Cyclic response element-binding protein and nerve growth factor/protein kinase B/Phospholipase C-Gamma signaling pathways. Biomed Biotechnol Res J 2023;7:24-31

How to cite this URL:
Gholami M, Emanuele E, Motaghinejad M. Constant romantic feelings and experiences can protect against neurodegeneration: Potential role of oxytocin-induced nerve growth factor/protein kinase B/Cyclic response element-binding protein and nerve growth factor/protein kinase B/Phospholipase C-Gamma signaling pathways. Biomed Biotechnol Res J [serial online] 2023 [cited 2023 Jun 10];7:24-31. Available from: https://www.bmbtrj.org/text.asp?2023/7/1/24/371691

Introduction

Neurodegeneration – defined as a progressive cell loss in specific neuronal populations – has devastating clinical consequences with significant societal and economic implications.^[1] In neurodegenerative disorders and disease, occurrences of oxidative stress, apoptosis, and inflammation which consequence from mitochondrial dysfunction, play critical roles^[2],[3],[4] [Figure 1]. Besides detrimental factors, recent years have witnessed a growing interest in mechanisms that can protect against or prevent neuronal loss. In this regard, both the hormone oxytocin and neurotrophic factors (NTFs) have been identified as potential neuroprotective molecules.^{[5],[6],[7],[8]} Romantic experiences – which are characterized by intense emotional intimacy – have complex biological underpinnings, including an increased production and release of oxytocin and nerve growth factor (NGF). Because both oxytocin and NGF can protect against neurodegeneration, we propose our hypothesis that being constantly engaged in romantic feelings and experiences may delay or even prevent the onset of neurodegenerative diseases (NDDs). We also propose that this could occur at the molecular level through the NGF/protein kinase B/cyclic response element-binding protein (NGF/Akt/CREB) and NGF/Akt/phospholipase C-gamma (NGF/Akt/PLC-γ) signaling pathways. In this article, we describe this conceptual framework and delineate potential avenues for future research in the field.

Figure 1: In neurodegenerative disorders and disease, occurrences of oxidative stress, apoptosis, and inflammation, which are consequences of mitochondrial dysfunction, have critical roles

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Oxytocin effects on the neural system

Oxytocin – which is popularly known as the “love hormone” [Figure 2] – is both a peptide hormone and a neuropeptide produced in the hypothalamus and released by the posterior pituitary.^[9],[10] Growing evidence has accrued that oxytocin is involved in social bonding, sexual reproduction, pregnancy, and breastfeeding.^[9],[11] In women, oxytocin is released into the bloodstream in response to stretching of the cervix and uterus during labor and to stimulation of the nipples during breastfeeding. This hormone response helps during childbirth, maternal bonding with the baby, and milk production.^{[11],[12],[13]} Several recent studies have shown that oxytocin has multiple effects on brain function.^{[14],[15],[16]} For example, this hormone relieves symptoms of anxiety and depression and can increase cognitive function and social behavior.^[17] Interestingly, oxytocin can also act as a neuroprotective factor that prevents mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal apoptosis.^{[18],[19],[20]} Oxytocin has the potential to protect against neurodegeneration through multiple behavior effects. Accordingly, this molecule boosts sexual arousal, crystallizes emotional memories, eases stress, solidifies relationships, promotes attachment, reduces drug cravings, triggers protective instincts, and induces braveness^{[20],[21],[22]} [Figure 3].

Figure 2: Structure of oxytocin

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Figure 3: Multiple neurochemical and neurobehavioral effects of oxytocin on the brain and Oxytocin can modulate behavioral effects such as boosts sexual arousal, crystallizes emotional memories, eases stress, solidifies relationships, promotes attachment, reduces drug cravings, triggers protective instincts, and induces braveness. Also causes inhibition of apoptosis, oxidative stress, inflammation, and mitochondrial dysfunction

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Remarkably, oxytocin release has been closely linked to a person's emotional state and romantic feelings during their lifetime.^{[22],[23],[24]} People in the first stages of romantic attachment had higher levels of oxytocin than nonattached single people and this increase persisted for at least 6 months.^[25],[26] Moreover, sexual activity has also been shown to stimulate the release of oxytocin, which appears to have a role in erection and orgasm.^[27],[28] There has been growing evidence showing that having a stable romantic relationship throughout a person's life may promote health and reduce the risk of neurological diseases.^{[29],[30],[31]} However, the complex interrelationships between oxytocin, neuroprotection, and romantic feelings have not yet been entirely elucidated and deserve further scrutiny.^{[29],[30],[31],[32]} In this scenario, one interesting and still underexplored possibility is that oxytocin may promote neuron survival by stimulating the synthesis and release of NTFs.^{[33],[34],[35]}

Neurotrophic factors and their role in neuronal development, survival, and maturation

NTFs – which are molecules that promote the growth and survival potential of neurons by signaling through tyrosine kinases,^[36] are known to play a critical role during central nervous system development, where they can act as guidance cues for developing neurons.^[36],[37] In the mature nervous system, NTFs promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories.^[37],[38] They also have the ability to promote the re-grow of damaged neurons in animal models. NTFs comprise three main families consisting of neurotrophins, glial cell-line derived NTF family ligands, and neuropoietic cytokines.^{[38],[39],[40]} Some important NTFs [Figure 4] are brain-derived neurotrophic factor (BDNF), NGF, glial cell line-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4^[40] [Figure 4].

Figure 4: Some important neurotrophic factors and their classification by their action in the growth, proliferation, and differentiation of brain cells

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Nerve growth factor signaling pathway and neuroprotection

NGF is an NTF and neuropeptide that is primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons.^[41] It is also critical for the survival and maintenance of sympathetic and sensory neurons, as they undergo apoptosis in their absence.^[42],[43] However, NGF may have pleiotropic – and at least in part still under-recognized – biological activity,^[44],[45] apart from its well-known role in protecting against oxidative stress, neuro-inflammation, and neuronal death.^{[46],[47],[48]} Current basic research indicates that NGF successfully prevents neurotoxicity, peripheral nerve injury, diabetic peripheral neuropathy, senile dementia, Parkinson's disease, facial neuritis, and neuronal damage.^{[49],[50],[51],[52]} In terms of the signaling pathway, by acting on its receptor tropomyosin receptor kinase A (TrkA), NGF causes activation of Akt in brain cells. By activating this protein, some important transcription factors, such as cyclic-adenosine monophosphate response element-binding protein (CREB), are activated. CREB has a critical role in the synaptic and survival of neurons and the regulation of BDNF gene expression.^{[52],[53],[54]} The activation of Akt causes the activation of PLC-γ. PLCγ is downstream of receptor tyrosine kinase and is responsive to neurotrophin/Trk action.^[55],[56] In the neuronal system, PLCγ is well characterized for its role in BDNF-initiated long-term potentiation, synaptic plasticity, and remodeling.^[57],[58] The function of PLCγ is mediated by IP₃-facilitated Ca²⁺ release from the intracellular store and/or diacylglycerol/protein kinase C-modulated ion channel activity, which leads to Ca²⁺ influx and an increase in intracellular Ca²⁺ ([Ca²⁺]_i) levels and activity of Ca²⁺-dependent pathways.^[59],[60] Subsequently, the transcription factor CREB, whose activity is dependent on Ca²⁺ levels, undergoes trafficking and phosphorylation, which promote gene transcription.^[61] Although other types of proteins and molecules are involved in the NGF function and signaling pathway, the NGF/Akt/CREB and NGF/Akt/PLC-γ signaling pathways are the most likely relevant for NGF-induced neuroprotection [Figure 5].

Figure 5: Although other types of proteins and molecules are involved in the NGF function and signaling pathway, NGF via TrkA receptor can activate Akt, which leads to the activation of CREB, and, consequently, the production of BDNF. NGF via TrkA receptor can activate Akt, which has a positive regulatory effect on BDNF function. NGF: Nerve growth factor, TrkA: Tropomyosin receptor kinase A Akt: Protein kinase B, CREB: Cyclic response element-binding protein, BDNF: Brain-derived neurotrophic factor

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Oxytocin-induced nerve growth factor/protein kinase B/cyclic response element-binding protein or nerve growth factor/protein kinase B/phospholipase C-gamma signaling pathway

Regarding the relation with oxytocin and NGF activity, previous studies demonstrated that oxytocin promotes nerve healing via activation of NGF and other NTFs.^{[33],[34],[35]} In addition, oxytocin-induced neurobehavioral and neurochemical effects are at least in part mediated by NGF.^[34],[62] Research has also demonstrated that during pregnancy, NGF is released into plasma by an oxytocin-mediated response.^[63] Some parts of neurogenesis and neurodevelopment processes, which occur via NGF mediation, are controlled directly and indirectly by oxytocin.^[33],[64] Regarding the detailed effects of oxytocin on NGF and the NGF downstream signaling pathways, such as NGF/Akt/CREB or NGF/Akt/PLC-γ, we hypothesize that oxytocin-induced NGF activation elicits the above-mentioned signaling mechanisms. Therefore, according to the published findings, we propose the hypothesis that having constant romantic feelings and experiences during a person's life can delay and event prevent the onset of NDDs. This protective effect can possibly be mediated by the oxytocin-induced NGF/Akt/CREB and NGF/Akt/PLC-γ signaling pathways. Below, we examine our hypothesis in detail.

Hypothesis

Romantic love promotes the production and secretion of both oxytocin and NGF in the bloodstream. Based on the interrelationships between oxytocin and NGF described above, we hypothesize that having a stable romantic life can delay or even prevent neurodegenerative events via the oxytocin-induced NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathways. In order to assess whether these hypotheses have been performed before searches on numerous databases, such as Scopus, PubMed, Web of Science, Google Scholar, Elsevier, Science Direct, Core Collection, and Cochrane, with the keywords romantic life or emotional life and neurodegeneration events, were performed to evaluate published data on the role of stable romantic or emotional life on the initiation and occurrence of neurodegeneration. We attempted to investigate the correlation between oxytocin and NGF and neurotoxicity and neurodegeneration. In particular, we focused on the possible role of oxytocin-induced NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathways as potential mediators. Because no relevant studies were identified, a working hypothesis is provided below.

Hypothesis and Its Testing

NDDs are incurable and cause progressive degeneration and/or death of neurons.^[54],[65] There are no direct evidence that show the effects of love and romantic life on NDDs, but based on some previous studies, it was demonstrated that feeling good and emotional well-being can inhibit occurrences of NDDs; based on this concept, it can be suggested that love can protect against NDDs through psychological resilience and emotional well-being,^{[66],[67],[68]} and probably, by this mechanism, it can be effective in management on incidence, occurrences and severity of NDDs, but this concept was not approved yet. Thus, based on this concept and with regard to our suggestion and hypothesis, we proposed that having constant romantic feelings and experiences during life can inhibit a neurodegenerative disorder. These effects were possibly mediated via oxytocin-induced NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathway.

Previous molecular results demonstrated the neuroprotective role of oxytocin in neural cell damage.^{[19],[20],[69],[70]} Some studies have shown that oxytocin treatment can inhibit occurrences of oxidative stress and inflammation.^{[19],[20],[69],[70]} Previous studies have demonstrated that oxytocin has neuroprotective efficacy.^[20] As mentioned above, psychological resilience and emotional well-being can hypothetically inhibit occurrences of NDD; on the other hand, it was demonstrated that oxytocin and probably NGF can be strong biological mediators of well-being,^{[66],[67],[68],[71],[72],[73]} thus it can be suggested that oxytocin and NGF in addition to their molecular effects and neuroprotective properties can behaviorally modules NDDs.

Some studies demonstrated that oxytocin antioxidant effects were mediated via lipid regulation and peroxidation.^[74],[75] Some parts of oxytocin act as an antioxidant, activate other protective free radical scavengers and are mediated via antioxidant enzymes, such as SOD, CAT, GR, and GPx.^[19],[75] Evidence shows that oxytocin can be a critical regulator of the glutathione pathway, which in neurodegenerative events, caused GSSG to be transformed into GSH.^[19],[75] The effects of oxytocin on the mitochondrial respiratory chain were suggested, but exact signaling pathways remain unclear.^[76],[77] With the positive effects of oxytocin against oxidative stress reduction, previous studies have demonstrated the effect of this agent on neural inflammatory signals.^[77],[78] Oxytocin can inhibit microglial activation during neuronal cell death and neurodegeneration.^[78],[79] Oxytocin can inhibit apoptosis occurrences and reduce the occurrence of cell death in neuronal cells, but its mechanism and involved signaling pathway remain unknown.^[80],[81] In addition to all aspects of the neuroprotective effects of oxytocin, studies have demonstrated that a release of and increase in this hormone depends on a person's emotional state and their romantic relationships throughout their life.^[9],[11] Thus, we can assume that having a romantic relationship throughout life, via the oxytocin effect; can be a suitable strategy for the inhibition of occurrences and continuous oxidative stress, inflammation, apoptosis, and neurodegeneration. However, this claim was not approved and is a hypothesis. A romantic relationship induced-oxytocin section and downstream signaling pathways for the possible neuroprotection of this hormone remain unclear and need further assessment.

Some studies attempted to clarify downstream the signaling pathways of oxytocin; this tried to clarify the role of oxytocin in the modulation of some NTFs, such as NGF. According to these results and this hormone confers its neuroprotective effects via NGF.^[33],[34] NGF is one of the main NTFs in the brain that regulates the growth, maintenance, proliferation, and survival of certain target neurons.^[41] The presence of NGF is critical for the survival and maintenance of normal neural function.^[41]

Previous studies reported that people in the first stages of romantic attachment had higher levels of oxytocin compared with nonattached single people. These levels persisted for at least 6 months.^[22] Sexual activity has been determined to stimulate the release of oxytocin and has a role in erection and orgasm, especially in men.^[82] The reason for this finding is not fully understood, but in women, increased uterine motility may help sperm to reach their destination. Some researchers have proposed a correlation between the concentration of oxytocin and the intensity of orgasm.^[83],[84] Consistent with this finding, some novel studies indicated that having a stable, romantic, and loving relationship throughout a person's life will help to reduce of occurrences and intensity of various diseases, especially neurological diseases and disorders.^[24],[85] Researchers have suggested that oxytocin can have a critical role in this neuroprotective effect of romantic life, but the mechanism and signaling pathway remain unclear and warrant further evaluation.^[24],[85] Some studies show the effects of oxytocin in the modulation of some NTFs, and the protective effects of these factors were demonstrated in various studies.^[86] The exact link among romantic life, oxytocin secretion and subsequent NTF secretion is still unknown and needs further investigation.

Many studies indicated that oxytocin release increased during romantic relationships.^{[22],[24],[85]} Research has strongly established that NGF levels and the activity of this NTF on its receptor were disturbed during neurodegenerative events; this phenomenon leads to significant neurodevelopmental disturbance and triggers neurodegenerative events.^[87],[88] A decrease or lack of NGF causes the initiation of neurodegenerative parameters, such as oxidative stress, inflammation, and apoptosis, as previously discussed.^[41],[89] Some studies demonstrated that oxytocin exerts its effects via activation of NGF, and these effects can be mediated by NGF action.^[34],[86] In addition to oxytocin, the NGF level also increased during constant romantic life and loving emotional relationship;^[62],[90] this concept confirms the correlation between oxytocin release and NGF levels.^[34],[86] According to the previously mentioned statement about the protective role of both oxytocin and NGF in the modulation of neurodegenerative events, a constant romantic life and loving emotional relationship may inhibit initiation and continuous neurodegenerative events, which can be modulated via the oxytocin-NGF pathway.

Although previous studies both directly and indirectly demonstrated that the oxytocin-NGF pathway can offer neuroprotection and inhibit cell death, the downstream signaling pathway of oxytocin-and also the role of NGF in the mediation of oxytocin effects remain ambiguous.^[86],[91] Previous studies indicated that NGF exerts its effects via major and strategic pathways, such as NGF/Akt/CREB or NGF/Akt/PLC-γ.^{[52],[53],[54],[92]} Regarding the oxytocin effects on NGF and the NGF downstream signaling pathway, such as NGF/Akt/CREB or NGF/Akt/PLC-γ, we can hypothesize that after oxytocin-induced NGF activation, the NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathways were activated, and subsequently neural development, neurogenesis, and neuroprotection occurred.^{[42],[52],[53],[54],[92],[93]} As mentioned above, psychological resilience and emotional well-being can hypothetically inhibit occurrences of NDD, probably via oxytocin and NGF, but this concept was not approved; also the role of NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathways in the mediation of psychological well-being was not approved yet. However, based on the mentioned protective role of oxytocin and NGF in the mediation of psychological resilience and emotional well-being, it seems that these NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathways probably have a positive role in the mediation of psychological resilience and emotional well-being. In other word, in addition to the mentioned protective role of mentioned signaling pathway on the inhibition of NDD, this pathway can also behaviorally modulates psychological resilience and emotional well-being and by this mechanism, also can inhibit NDDs.

After activation of the TrkA receptor by NGF, Akt phosphorylation (activation) occurred in brain cells which lead to CREB/BDNF activation and alteration of gene expression.^[42],[94] Molecular biology reports indicate that NGF-Akt-CREB/BDNF positive feedback has a critical role in modulation cell survival.^[94] These reports indicated that any kind of disturbance in this pathway can cause occurrences of malicious events, such as oxidative stress, inflammation, and apoptosis, which can lead to neurodegeneration.^[95],[96] NGF by activation of Akt causes activation of PLC-γ, which leads to BDNF-initiated long-term potentiation, synaptic plasticity, remodeling and neural survival.^{[42],[52],[53],[54],[92],[93]} PLCγ also has a critical role in IP₃-facilitated CREB activation and promotes BDNF gene transcription.^[57],[58] Although other types of proteins and molecules are involved in the NGF function and signaling pathway, it seems that the NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathway is more important in NGF-induced neuroprotection during neurodegeneration events.^{[42],[52],[53],[54],[92],[93]} NGF by activation of Akt causes inactivation of glycogen synthase kinase 3β, which prevents some malicious neurobehavioral and neurochemical activity.^[92]

According to the literature reports mentioned in this study, having a constant romantic life and loving emotional relationship throughout a person's life constitutes protective behavior against the initiation and continuation of neurodegenerative events. The findings suggest that romantic behaviors induce oxytocin and NGF secretion and activation and that by its downstream signaling pathways, such as NGF/Akt/CREB or NGF/Akt/PLC-γ, NGF can have a strategic role in the neuroprotective effects of this beneficial behavior [Figure 6]. To prove of this claim in future studies, it can be also suggested the evaluation of expression of NGF/Akt/CREB or NGF/Akt/PLC-γ signaling pathways during love and its relation to occurrences of NDDs can be considered.

Figure 6: Romantic behaviors induce oxytocin and NGF secretion and activation and modulate their effect. Probably by its downstream signaling pathway, such as NGF/Akt/CREB or NGF/Akt/PLC-γ, NGF can have a strategic role in the neuroprotective effects of this beneficial behavior. NGF/Akt/CREB: Nerve growth factor/protein kinase B/cyclic response element-binding protein, NGF/Akt/PLC-γ: Nerve growth factor/protein kinase B/phospholipase C-gamma

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Perneczky R, Kempermann G, Korczyn AD, Matthews FE, Ikram MA, Scarmeas N, et al. Translational research on reserve against neurodegenerative disease: Consensus report of the International Conference on Cognitive Reserve in the Dementias and the Alzheimer's Association Reserve, Resilience and Protective Factors Professional Interest Area working groups. BMC Med 2019;17:47.
2.	Amor S, Puentes F, Baker D, van der Valk P. Inflammation in neurodegenerative diseases. Immunology 2010;129:154-69.
3.	Griffin WS. Inflammation and neurodegenerative diseases. Am J Clin Nutr 2006;83:470S-4S.
4.	Friedlander RM. Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 2003;348:1365-75.
5.	Freland L, Beaulieu JM. Inhibition of GSK3 by lithium, from single molecules to signaling networks. Front Mol Neurosci 2012;5:14.
6.	Kitagishi Y, Kobayashi M, Kikuta K, Matsuda S. Roles of PI3K/AKT/GSK3/mTOR pathway in cell signaling of mental illnesses. Depress Res Treat 2012;2012:752563.
7.	Meffre D, Massaad C, Grenier J. Lithium chloride stimulates PLP and MBP expression in oligodendrocytes via Wnt/β-catenin and Akt/CREB pathways. Neuroscience 2015;284:962-71.
8.	Malhi GS, Outhred T. Therapeutic mechanisms of lithium in bipolar disorder: Recent advances and current understanding. CNS Drugs 2016;30:931-49.
9.	Scheele D, Wille A, Kendrick KM, Stoffel-Wagner B, Becker B, Güntürkün O, et al. Oxytocin enhances brain reward system responses in men viewing the face of their female partner. Proc Natl Acad Sci U S A 2013;110:20308-13.
10.	Carter CS, Porges SW. The biochemistry of love: An oxytocin hypothesis. EMBO Rep 2013;14:12-6.
11.	Uvnäs-Moberg K, Ekström-Bergström A, Berg M, Buckley S, Pajalic Z, Hadjigeorgiou E, et al. Maternal plasma levels of oxytocin during physiological childbirth – A systematic review with implications for uterine contractions and central actions of oxytocin. BMC Pregnancy Childbirth 2019;19:285.
12.	Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K, Heinrichs M, et al. Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 2010;35:83-93.
13.	White-Traut R, Watanabe K, Pournajafi-Nazarloo H, Schwertz D, Bell A, Carter CS. Detection of salivary oxytocin levels in lactating women. Dev Psychobiol 2009;51:367-73.
14.	Gordon I, Vander Wyk BC, Bennett RH, Cordeaux C, Lucas MV, Eilbott JA, et al. Oxytocin enhances brain function in children with autism. Proc Natl Acad Sci U S A 2013;110:20953-8.
15.	Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, et al. Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci 2005;25:11489-93.
16.	Bethlehem RA, van Honk J, Auyeung B, Baron-Cohen S. Oxytocin, brain physiology, and functional connectivity: A review of intranasal oxytocin fMRI studies. Psychoneuroendocrinology 2013;38:962-74.
17.	Cochran DM, Fallon D, Hill M, Frazier JA. The role of oxytocin in psychiatric disorders: A review of biological and therapeutic research findings. Harv Rev Psychiatry 2013;21:219-47.
18.	Ceanga M, Spataru A, Zagrean AM. Oxytocin is neuroprotective against oxygen-glucose deprivation and reoxygenation in immature hippocampal cultures. Neurosci Lett 2010;477:15-8.
19.	Karelina K, Stuller KA, Jarrett B, Zhang N, Wells J, Norman GJ, et al. Oxytocin mediates social neuroprotection after cerebral ischemia. Stroke 2011;42:3606-11.
20.	Vargas-Martínez F, Uvnäs-Moberg K, Petersson M, Olausson HA, Jiménez-Estrada I. Neuropeptides as neuroprotective agents: Oxytocin a forefront developmental player in the mammalian brain. Prog Neurobiol 2014;123:37-78.
21.	Levin R, Edelman S, Shalev I, Ebstein RP, Heresco-Levy U. The role of oxytocin in neuropsychiatric disorders: Concepts and mechanisms. In: Brain Protection in Schizophrenia, Mood and Cognitive Disorders. Berlin/Heidelberg, Germany: Springer; 2010. p. 611-35.
22.	Marazziti D, Dell'Osso B, Baroni S, Mungai F, Catena M, Rucci P, et al. A relationship between oxytocin and anxiety of romantic attachment. Clin Pract Epidemiol Ment Health 2006;2:28.
23.	Grebe NM, Kristoffersen AA, Grøntvedt TV, Emery Thompson M, Kennair LE, Gangestad SW. Oxytocin and vulnerable romantic relationships. Horm Behav 2017;90:64-74.
24.	Lee HJ, Macbeth AH, Pagani JH, Young WS 3^rd. Oxytocin: The great facilitator of life. Prog Neurobiol 2009;88:127-51.
25.	Bartz JA, Zaki J, Bolger N, Ochsner KN. Social effects of oxytocin in humans: Context and person matter. Trends Cogn Sci 2011;15:301-9.
26.	Earp BD, Savulescu J. Wonder hormone. In: Love is the Drug. England: Manchester University Press; 2020.
27.	Neumann ID. Brain oxytocin: A key regulator of emotional and social behaviours in both females and males. J Neuroendocrinol 2008;20:858-65.
28.	Magon N, Kalra S. The orgasmic history of oxytocin: Love, lust, and labor. Indian J Endocrinol Metab 2011;15 Suppl 3:S156-61.
29.	Fisher HE, Aron A, Brown LL. Romantic love: A mammalian brain system for mate choice. Philos Trans R Soc Lond B Biol Sci 2006;361:2173-86.
30.	Acevedo BP, Aron A, Fisher HE, Brown LL. Neural correlates of long-term intense romantic love. Soc Cogn Affect Neurosci 2012;7:145-59.
31.	Song S, Zou Z, Song H, Wang Y, d'Oleire Uquillas F, Wang H, et al. Romantic love is associated with enhanced inhibitory control in an emotional stop-signal task. Front Psychol 2016;7:1574.
32.	Tom N, Assinder SJ. Oxytocin in health and disease. Int J Biochem Cell Biol 2010;42:202-5.
33.	Camerino C, Conte E, Carratù MR, Fonzino A, Lograno MD, Tricarico D. Oxytocin/osteocalcin/IL-6 and NGF/BDNF mRNA levels in response to cold stress challenge in mice: Possible oxytonic brain-bone-muscle-interaction. Front Physiol 2019;10:1437.
34.	Gümüs B, Kuyucu E, Erbas O, Kazimoglu C, Oltulu F, Bora OA. Effect of oxytocin administration on nerve recovery in the rat sciatic nerve damage model. J Orthop Surg Res 2015;10:161.
35.	Bale TL, Dorsa DM. NGF, cyclic AMP, and phorbol esters regulate oxytocin receptor gene transcription in SK-N-SH and MCF7 cells. Brain Res Mol Brain Res 1998;53:130-7.
36.	Fumagalli F, Molteni R, Calabrese F, Maj PF, Racagni G, Riva MA. Neurotrophic factors in neurodegenerative disorders: Potential for therapy. CNS Drugs 2008;22:1005-19.
37.	Bartus RT, Baumann TL, Brown L, Kruegel BR, Ostrove JM, Herzog CD. Advancing neurotrophic factors as treatments for age-related neurodegenerative diseases: Developing and demonstrating “clinical proof-of-concept” for AAV-neurturin (CERE-120) in Parkinson's disease. Neurobiol Aging 2013;34:35-61.
38.	Salehi A, Delcroix JD, Mobley WC. Traffic at the intersection of neurotrophic factor signaling and neurodegeneration. Trends Neurosci 2003;26:73-80.
39.	Markus A, Patel TD, Snider WD. Neurotrophic factors and axonal growth. Curr Opin Neurobiol 2002;12:523-31.
40.	Levy YS, Gilgun-Sherki Y, Melamed E, Offen D. Therapeutic potential of neurotrophic factors in neurodegenerative diseases. BioDrugs 2005;19:97-127.
41.	Sofroniew MV, Howe CL, Mobley WC. Nerve growth factor signaling, neuroprotection, and neural repair. Annu Rev Neurosci 2001;24:1217-81.
42.	Patel TD, Jackman A, Rice FL, Kucera J, Snider WD. Development of sensory neurons in the absence of NGF/TrkA signaling in vivo. Neuron 2000;25:345-57.
43.	Budni J, Bellettini-Santos T, Mina F, Garcez ML, Zugno AI. The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease. Aging Dis 2015;6:331-41.
44.	Zhang Y, Moheban DB, Conway BR, Bhattacharyya A, Segal RA. Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J Neurosci 2000;20:5671-8.
45.	O'Keeffe GW, Gutierrez H, Pandolfi PP, Riccardi C, Davies AM. NGF-promoted axon growth and target innervation requires GITRL-GITR signaling. Nat Neurosci 2008;11:135-42.
46.	Bianco MR, Berbenni M, Amara F, Viggiani S, Fragni M, Galimberti V, et al. Cross-talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells. J Neurosci Res 2011;89:1302-15.
47.	Onyango IG, Ahn JY, Tuttle JB, Bennett JP Jr., Swerdlow RH. Nerve growth factor attenuates oxidant-induced β-amyloid neurotoxicity in sporadic Alzheimer's disease cybrids. J Neurochem 2010;114:1605-18.
48.	Carito V, Pingitore A, Cione E, Perrotta I, Mancuso D, Russo A, et al. Localization of nerve growth factor (NGF) receptors in the mitochondrial compartment: Characterization and putative role. Biochim Biophys Acta 2012;1820:96-103.
49.	Heaton MB, Mitchell JJ, Paiva M. Overexpression of NGF ameliorates ethanol neurotoxicity in the developing cerebellum. J Neurobiol 2000;45:95-104.
50.	Lan Z, Chen L, Fu Q, Ji W, Wang S, Liang Z, et al. Paeoniflorin attenuates amyloid-beta peptide-induced neurotoxicity by ameliorating oxidative stress and regulating the NGF-mediated signaling in rats. Brain Res 2013;1498:9-19.
51.	Colafrancesco V, Villoslada P. Targeting NGF pathway for developing neuroprotective therapies for multiple sclerosis and other neurological diseases. Arch Ital Biol 2011;149:183-92.
52.	Wang ZG, Li H, Huang Y, Li R, Wang XF, Yu LX, et al. Nerve growth factor-induced Akt/mTOR activation protects the ischemic heart via restoring autophagic flux and attenuating ubiquitinated protein accumulation. Oncotarget 2017;8:5400-13.
53.	Xie Y, Tisi MA, Yeo TT, Longo FM. Nerve growth factor (NGF) loop 4 dimeric mimetics activate ERK and AKT and promote NGF-like neurotrophic effects. J Biol Chem 2000;275:29868-74.
54.	Kandezi N, Mohammadi M, Ghaffari M, Gholami M, Motaghinejad M, Safari S. Novel insight to neuroprotective potential of curcumin: A mechanistic review of possible involvement of mitochondrial biogenesis and PI3/Akt/GSK3 or PI3/Akt/CREB/BDNF signaling pathways. Int J Mol Cell Med 2020;9:1-32.
55.	Choi DY, Toledo-Aral JJ, Segal R, Halegoua S. Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. Mol Cell Biol 2001;21:2695-705.
56.	Nguyen Tle X, Ahn JY. Lipase inactive mutant of PLC-gamma1 regulates NGF-induced neurite outgrowth via enzymatic activity and regulation of cell cycle regulatory proteins. J Biochem Mol Biol 2007;40:888-94.
57.	Kiss K, Salamon S, Töröcsik B, Szeberényi J. Role of phospholipase C-gamma in NGF-stimulated differentiation and gene induction. Acta Biol Hung 2006;57:147-55.
58.	Rose CR, Blum R, Kafitz KW, Kovalchuk Y, Konnerth A. From modulator to mediator: Rapid effects of BDNF on ion channels. Bioessays 2004;26:1185-94.
59.	Thillaiappan NB, Chakraborty P, Hasan G, Taylor CW. IP (3) receptors and Ca (2+) entry. Biochim Biophys Acta Mol Cell Res 2019;1866:1092-100.
60.	Berridge MJ. The inositol trisphosphate/calcium signaling pathway in health and disease. Physiol Rev 2016;96:1261-96.
61.	Cartin L, Lounsbury KM, Nelson MT. Coupling of Ca (2+) to CREB activation and gene expression in intact cerebral arteries from mouse: Roles of ryanodine receptors and voltage-dependent Ca (2+) channels. Circ Res 2000;86:760-7.
62.	Emanuele E. NGF and romantic love. Arch Ital Biol 2011;149:265-8.
63.	Luppi P, Levi-Montalcini R, Bracci-Laudiero L, Bertolini A, Arletti R, Tavernari D, et al. NGF is released into plasma during human pregnancy: An oxytocinmediated response? In: The Saga of the Nerve Growth Factor: Preliminary Studies, Discovery, Further Development: Singapore. World Scientific 1997:439-41.
64.	Bakos J, Strbak V, Ratulovska N, Bacova Z. Effect of oxytocin on neuroblastoma cell viability and growth. Cell Mol Neurobiol 2012;32:891-6.
65.	Kermanshahi S, Ghanavati G, Abbasi-Mesrabadi M, Gholami M, Ulloa L, Motaghinejad M, et al. Novel neuroprotective potential of crocin in neurodegenerative disorders: An illustrated mechanistic review. Neurochem Res 2020;45:2573-85.
66.	Levenson RW, Sturm VE, Haase CM. Emotional and behavioral symptoms in neurodegenerative disease: A model for studying the neural bases of psychopathology. Annu Rev Clin Psychol 2014;10:581-606.
67.	Demange M, Lenoir H, Pino M, Cantegreil-Kallen I, Rigaud AS, Cristancho-Lacroix V. Improving well-being in patients with major neurodegenerative disorders: Differential efficacy of brief social robot-based intervention for 3 neuropsychiatric profiles. Clin Interv Aging 2018;13:1303-11.
68.	Esch T, Stefano GB. The neurobiological link between compassion and love. Med Sci Monit 2011;17:A65-75.
69.	Etehadi Moghadam S, Azami Tameh A, Vahidinia Z, Atlasi MA, Hassani Bafrani H, Naderian H. Neuroprotective effects of oxytocin hormone after an experimental stroke model and the possible role of calpain-1. J Stroke Cerebrovasc Dis 2018;27:724-32.
70.	Kaneko Y, Pappas C, Tajiri N, Borlongan CV. Oxytocin modulates GABA (A) R subunits to confer neuroprotection in stroke in vitro. Sci Rep 2016;6:35659.
71.	Kalisch R, Müller MB, Tüscher O. A conceptual framework for the neurobiological study of resilience. Behav Brain Sci 2015;38:e92.
72.	Uvnas-Moberg K, Petersson M. Oxytocin, a mediator of anti-stress, well-being, social interaction, growth and healing. Z Psychosom Med Psychother 2005;51:57-80.
73.	Cuello AC, Pentz R, Hall H. The brain NGF metabolic pathway in health and in Alzheimer's pathology. Front Neurosci 2019;13:62.
74.	Işeri SO, Sener G, Sağlam B, Gedik N, Ercan F, Yeğen BC. Oxytocin ameliorates oxidative colonic inflammation by a neutrophil-dependent mechanism. Peptides 2005;26:483-91.
75.	Wang Y, Zhao S, Liu X, Zheng Y, Li L, Meng S. Oxytocin improves animal behaviors and ameliorates oxidative stress and inflammation in autistic mice. Biomed Pharmacother 2018;107:262-9.
76.	Bordt EA, Smith CJ, Demarest TG, Bilbo SD, Kingsbury MA. Mitochondria, oxytocin, and vasopressin: Unfolding the inflammatory protein response. Neurotox Res 2019;36:239-56.
77.	Amini-Khoei H, Mohammadi-Asl A, Amiri S, Hosseini MJ, Momeny M, Hassanipour M, et al. Oxytocin mitigated the depressive-like behaviors of maternal separation stress through modulating mitochondrial function and neuroinflammation. Prog Neuropsychopharmacol Biol Psychiatry 2017;76:169-78.
78.	Inoue T, Yamakage H, Tanaka M, Kusakabe T, Shimatsu A, Satoh-Asahara N. Oxytocin suppresses inflammatory responses induced by lipopolysaccharide through inhibition of the eIF-2-ATF4 pathway in mouse microglia. Cells 2019;8:527.
79.	Yuan L, Liu S, Bai X, Gao Y, Liu G, Wang X, et al. Oxytocin inhibits lipopolysaccharide-induced inflammation in microglial cells and attenuates microglial activation in lipopolysaccharide-treated mice. J Neuroinflammation 2016;13:77.
80.	Latt HM, Matsushita H, Morino M, Koga Y, Michiue H, Nishiki T, et al. Oxytocin inhibits corticosterone-induced apoptosis in primary hippocampal neurons. Neuroscience 2018;379:383-9.
81.	Erbaş O, Oltulu F, Taşkiran D. Amelioration of rotenone-induced dopaminergic cell death in the striatum by oxytocin treatment. Peptides 2012;38:312-7.
82.	Kendrick KM. Oxytocin, motherhood and bonding. Exp Physiol 2000;85:111S-24S.
83.	Carter CS. Oxytocin and sexual behavior. Neurosci Biobehav Rev 1992;16:131-44.
84.	Caruso S, Mauro D, Scalia G, Palermo CI, Rapisarda AM, Cianci A. Oxytocin plasma levels in orgasmic and anorgasmic women. Gynecol Endocrinol 2018;34:69-72.
85.	Schneiderman I, Zagoory-Sharon O, Leckman JF, Feldman R. Oxytocin during the initial stages of romantic attachment: Relations to couples' interactive reciprocity. Psychoneuroendocrinology 2012;37:1277-85.
86.	Bakos J, Srancikova A, Havranek T, Bacova Z. Molecular mechanisms of oxytocin signaling at the synaptic connection. Neural Plast 2018;2018:4864107.
87.	Allen SJ, Watson JJ, Shoemark DK, Barua NU, Patel NK. GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol Ther 2013;138:155-75.
88.	Covaceuszach S, Capsoni S, Ugolini G, Spirito F, Vignone D, Cattaneo A. Development of a non invasive NGF-based therapy for Alzheimer's disease. Curr Alzheimer Res 2009;6:158-70.
89.	Lorigados L, Molina H, Serrano T, Pavón N, Robinson MA, Alvarez L, et al. Evolutive levels of NGF in neurodegenerative disorders. Mol Chem Neuropathol 1995;24:231-4.
90.	Emanuele E, Politi P, Bianchi M, Minoretti P, Bertona M, Geroldi D. Raised plasma nerve growth factor levels associated with early-stage romantic love. Psychoneuroendocrinology 2006;31:288-94.
91.	Chatterjee O, Patil K, Sahu A, Gopalakrishnan L, Mol P, Advani J, et al. An overview of the oxytocin-oxytocin receptor signaling network. J Cell Commun Signal 2016;10:355-60.
92.	Li K, Shi X, Luo M, Inam-U-LIah, Wu P, Zhang M, et al. Taurine protects against myelin damage of sciatic nerve in diabetic peripheral neuropathy rats by controlling apoptosis of schwann cells via NGF/Akt/GSK3β pathway. Exp Cell Res 2019;383:111557.
93.	Jiang L, Ye B, Wang Y, Yu T, Xu H. Effect and mechanisms of sacral nerve stimulation on visceral hypersensitivity mediated by nerve growth factor. J Cell Mol Med 2019;23:8019-24.
94.	Wang C, Liu Y, Ma W. Nerve growth factor regulates the proliferation of cashmere goat outer root sheath cells through the activation of cAMP-binding protein. Small Rumin Res 2019;178:30-6.
95.	Motaghinejad M, Motevalian M, Babalouei F, Abdollahi M, Heidari M, Madjd Z. Possible involvement of CREB/BDNF signaling pathway in neuroprotective effects of topiramate against methylphenidate induced apoptosis, oxidative stress and inflammation in isolated hippocampus of rats: Molecular, biochemical and histological evidences. Brain Res Bull 2017;132:82-98.
96.	Motaghinejad M, Farokhi N, Motevalian M, Safari S. Molecular, histological and behavioral evidences for neuroprotective effects of minocycline against nicotine-induced neurodegeneration and cognition impairment: Possible role of CREB-BDNF signaling pathway. Behav Brain Res 2020;386:112597.