|Year : 2023 | Volume
| 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|
Masih Daneshvari Hospital, Darabad Avenue, Shahid Bahonar Roundabout, Tehran
Source of Support: None, Conflict of Interest: None
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 Apr 1];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. In neurodegenerative disorders and disease, occurrences of oxidative stress, apoptosis, and inflammation which consequence from mitochondrial dysfunction, play critical roles,, [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.,,, 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., Growing evidence has accrued that oxytocin is involved in social bonding, sexual reproduction, pregnancy, and breastfeeding., 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.,, Several recent studies have shown that oxytocin has multiple effects on brain function.,, For example, this hormone relieves symptoms of anxiety and depression and can increase cognitive function and social behavior. Interestingly, oxytocin can also act as a neuroprotective factor that prevents mitochondrial dysfunction, oxidative stress, neuroinflammation, and neuronal apoptosis.,, 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,, [Figure 3].
|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.,, 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., Moreover, sexual activity has also been shown to stimulate the release of oxytocin, which appears to have a role in erection and orgasm., 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.,, However, the complex interrelationships between oxytocin, neuroprotection, and romantic feelings have not yet been entirely elucidated and deserve further scrutiny.,,, In this scenario, one interesting and still underexplored possibility is that oxytocin may promote neuron survival by stimulating the synthesis and release of NTFs.,,
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, are known to play a critical role during central nervous system development, where they can act as guidance cues for developing neurons., In the mature nervous system, NTFs promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories., 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.,, Some important NTFs [Figure 4] are brain-derived neurotrophic factor (BDNF), NGF, glial cell line-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 [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. It is also critical for the survival and maintenance of sympathetic and sensory neurons, as they undergo apoptosis in their absence., However, NGF may have pleiotropic – and at least in part still under-recognized – biological activity,, apart from its well-known role in protecting against oxidative stress, neuro-inflammation, and neuronal death.,, 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.,,, 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.,, The activation of Akt causes the activation of PLC-γ. PLCγ is downstream of receptor tyrosine kinase and is responsive to neurotrophin/Trk action., In the neuronal system, PLCγ is well characterized for its role in BDNF-initiated long-term potentiation, synaptic plasticity, and remodeling., 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., Subsequently, the transcription factor CREB, whose activity is dependent on Ca2+ levels, undergoes trafficking and phosphorylation, which promote gene transcription. 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.,, In addition, oxytocin-induced neurobehavioral and neurochemical effects are at least in part mediated by NGF., Research has also demonstrated that during pregnancy, NGF is released into plasma by an oxytocin-mediated response. Some parts of neurogenesis and neurodevelopment processes, which occur via NGF mediation, are controlled directly and indirectly by oxytocin., 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., 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,,, 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.,,, Some studies have shown that oxytocin treatment can inhibit occurrences of oxidative stress and inflammation.,,, Previous studies have demonstrated that oxytocin has neuroprotective efficacy. 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,,,,,, 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., 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., Evidence shows that oxytocin can be a critical regulator of the glutathione pathway, which in neurodegenerative events, caused GSSG to be transformed into GSH., The effects of oxytocin on the mitochondrial respiratory chain were suggested, but exact signaling pathways remain unclear., With the positive effects of oxytocin against oxidative stress reduction, previous studies have demonstrated the effect of this agent on neural inflammatory signals., Oxytocin can inhibit microglial activation during neuronal cell death and neurodegeneration., Oxytocin can inhibit apoptosis occurrences and reduce the occurrence of cell death in neuronal cells, but its mechanism and involved signaling pathway remain unknown., 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., 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., NGF is one of the main NTFs in the brain that regulates the growth, maintenance, proliferation, and survival of certain target neurons. The presence of NGF is critical for the survival and maintenance of normal neural function.
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. Sexual activity has been determined to stimulate the release of oxytocin and has a role in erection and orgasm, especially in men. 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., 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., 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., 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. 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.,, 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., A decrease or lack of NGF causes the initiation of neurodegenerative parameters, such as oxidative stress, inflammation, and apoptosis, as previously discussed., Some studies demonstrated that oxytocin exerts its effects via activation of NGF, and these effects can be mediated by NGF action., In addition to oxytocin, the NGF level also increased during constant romantic life and loving emotional relationship;, this concept confirms the correlation between oxytocin release and NGF levels., 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., Previous studies indicated that NGF exerts its effects via major and strategic pathways, such as NGF/Akt/CREB or NGF/Akt/PLC-γ.,,, 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.,,,,, 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., Molecular biology reports indicate that NGF-Akt-CREB/BDNF positive feedback has a critical role in modulation cell survival. 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., NGF by activation of Akt causes activation of PLC-γ, which leads to BDNF-initiated long-term potentiation, synaptic plasticity, remodeling and neural survival.,,,,, PLCγ also has a critical role in IP3-facilitated CREB activation and promotes BDNF gene transcription., 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.,,,,, NGF by activation of Akt causes inactivation of glycogen synthase kinase 3β, which prevents some malicious neurobehavioral and neurochemical activity.
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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Conflicts of interest
There are no conflicts of interest.
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