Figure 3 - uploaded by Armen N Akopian
Content may be subject to copyright.
Schematic of cellular signaling pathways via PrLr-L and PrLr-S in neurons. PrLr long (PrLr-L) and PrLr short (PrLr-S) isoforms control different signaling pathways in neurons. PrLr-L, but not PrLr-S activates JAK/STAT5 and Src kinase (i.e., Fyn) pathways. MAPK is probably activated by both isoforms. Pi3 and PKC kinases are likely activated by PrLr-S in neurons. PrLr-S mediated pathways are critical for rapid modulation of neuronal functions. Activation of neurons by PrL undergo via unknown pathways, which may involve PKC.
Source publication
Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by re...
Contexts in source publication
Context 1
... mechanism. 56 Interestingly, non-neuronal cells can be activated by PRL concentrations as low as 1nM. 63,65 Activation of neurons can lead to action potential firing, membrane channel activated by PRL (see above). 63 In neurons, it is presumed that PRL can produce Ca 2+ influx via both TRP-like channels and L-type voltage-gated Ca 2+ channels (Fig. 3). 58 The role of intracellular stores in PRL-evoked [ ...
Context 2
... control and endpoints such as cell differentiation, proliferation and survival of non-neuronal cells are relatively well studied. 2 There is a general agreement that a majority of these long-lasting PRL effects in non-neuronal as well as neuronal cells are mediated via PRLR-L and a recruitment of the JAK/STAT5 pathway or at times the MAPK pathway (Fig. 3). 1 Multiple studies performed in the nervous system suggest that besides long-lasting effects, neuronal responses to PRL can also be as fast as 1-5 min. 8,40,56,58 These rapid responses are essential for the control of neuronal excitability as well as modulation of neuronal circuitries by PRL. In this section, we will present current ...
Context 3
... sequence (30 aa) that does not contain any noticeable motifs for activation of kinases. This could suggest that perhaps both PRLR-L and PRLR-S have the potential for rapid signaling. However, this capability is suppressed for PRLR-L homodimers. Altogether, the rapid PRL effects in neurons could be mediated mainly by the PRLR-S homodimer (Fig. 3), which is extensively expressed in the nervous system (see Table 1). In sensory neurons, expressions of PRLR-L and PRLR-S seldom overlap. 40 In the CNS, PRLR-L, and PRLR-S expression overlaps are common. 48,49 In such circumstances, it is not clear which cellular mechanisms are responsible for separating the effects of PRLR-L and ...
Context 4
... PRL (0.01-1ug/ml) regulation of hypothalamic neuroendocrine dopaminergic (NEDA) neurons demonstrated that PRL rapidly induces synthesis of catecholamine via protein kinase A (PKA) and C (PKC), but not Ca 2+ -dependent calmodulin kinase-II (CaMKII) pathways. 77 PRL application also led to a PKCdependent activation of ERK1/2 within the MAPK pathway (Fig. 3). 77 Interestingly, PRL-activated transcription does not involve PKA, PKC, CaMKII, or ERK1/2 77 . The role of PRLtriggered rapid signaling pathways in neurons was further studied in TRPV1 sensitization. Inhibition of several kinase pathways demonstrated that the transient actions of PRL on TRPV1 activities in sensory neurons are ...
Context 5
... PRL-activated transcription does not involve PKA, PKC, CaMKII, or ERK1/2 77 . The role of PRLtriggered rapid signaling pathways in neurons was further studied in TRPV1 sensitization. Inhibition of several kinase pathways demonstrated that the transient actions of PRL on TRPV1 activities in sensory neurons are directed by PI3-kinase or PKC (Fig. 3). 40 PKA and Src-kinase inhibitors however failed to affect TRPV1 activity enhancement by PRL. 40 Detailed investigation showed that the main PKC isoform involved in mediating PRL effects on TRPV1 in sensory neurons is PKCε 40 . However, it is not clear whether the PKC pathway is downstream of the PI3-kinase pathway (Fig. 3). Rapid ...
Context 6
... by PI3-kinase or PKC (Fig. 3). 40 PKA and Src-kinase inhibitors however failed to affect TRPV1 activity enhancement by PRL. 40 Detailed investigation showed that the main PKC isoform involved in mediating PRL effects on TRPV1 in sensory neurons is PKCε 40 . However, it is not clear whether the PKC pathway is downstream of the PI3-kinase pathway (Fig. 3). Rapid induction of PI3-kinase by PRL in neurons of the CNS has been reported, and includes the suppression of BK-type Ca 2+ -dependent K + -currents in TIDA neurons by way of the PI3-kinase pathway (Fig. 3). 58 In summary, it appears that PRL activates two principally distinct signaling pathways in neurons. The first involves PRLR-L ...
Context 7
... effects on TRPV1 in sensory neurons is PKCε 40 . However, it is not clear whether the PKC pathway is downstream of the PI3-kinase pathway (Fig. 3). Rapid induction of PI3-kinase by PRL in neurons of the CNS has been reported, and includes the suppression of BK-type Ca 2+ -dependent K + -currents in TIDA neurons by way of the PI3-kinase pathway (Fig. 3). 58 In summary, it appears that PRL activates two principally distinct signaling pathways in neurons. The first involves PRLR-L and the phosphorylation of STAT5, leading to long-lasting effects based on transcription activation (Fig. 3). The second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, ...
Context 8
... the suppression of BK-type Ca 2+ -dependent K + -currents in TIDA neurons by way of the PI3-kinase pathway (Fig. 3). 58 In summary, it appears that PRL activates two principally distinct signaling pathways in neurons. The first involves PRLR-L and the phosphorylation of STAT5, leading to long-lasting effects based on transcription activation (Fig. 3). The second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, with subsequent modulation of neuronal channels, excitability and neurotransmission (Fig. 3). The schematic presented in Figure 3 is a simplified pathway, but underscores the primary signaling events following activation of neurons by ...
Context 9
... signaling pathways in neurons. The first involves PRLR-L and the phosphorylation of STAT5, leading to long-lasting effects based on transcription activation (Fig. 3). The second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, with subsequent modulation of neuronal channels, excitability and neurotransmission (Fig. 3). The schematic presented in Figure 3 is a simplified pathway, but underscores the primary signaling events following activation of neurons by endogenous or exogenous PRL. PI3-kinase, PKC and ERK1/2 can regulate a variety of ligand-and voltage-gated channels in neurons. Thus, PKC activation results in production of diacylglycerol (DAG), ...
Context 10
... second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, with subsequent modulation of neuronal channels, excitability and neurotransmission (Fig. 3). The schematic presented in Figure 3 is a simplified pathway, but underscores the primary signaling events following activation of neurons by endogenous or exogenous PRL. PI3-kinase, PKC and ERK1/2 can regulate a variety of ligand-and voltage-gated channels in neurons. ...
Context 11
... mechanism. 56 Interestingly, non-neuronal cells can be activated by PRL concentrations as low as 1nM. 63,65 Activation of neurons can lead to action potential firing, membrane channel activated by PRL (see above). 63 In neurons, it is presumed that PRL can produce Ca 2+ influx via both TRP-like channels and L-type voltage-gated Ca 2+ channels (Fig. 3). 58 The role of intracellular stores in PRL-evoked [ ...
Context 12
... control and endpoints such as cell differentiation, proliferation and survival of non-neuronal cells are relatively well studied. 2 There is a general agreement that a majority of these long-lasting PRL effects in non-neuronal as well as neuronal cells are mediated via PRLR-L and a recruitment of the JAK/STAT5 pathway or at times the MAPK pathway (Fig. 3). 1 Multiple studies performed in the nervous system suggest that besides long-lasting effects, neuronal responses to PRL can also be as fast as 1-5 min. 8,40,56,58 These rapid responses are essential for the control of neuronal excitability as well as modulation of neuronal circuitries by PRL. In this section, we will present current ...
Context 13
... sequence (30 aa) that does not contain any noticeable motifs for activation of kinases. This could suggest that perhaps both PRLR-L and PRLR-S have the potential for rapid signaling. However, this capability is suppressed for PRLR-L homodimers. Altogether, the rapid PRL effects in neurons could be mediated mainly by the PRLR-S homodimer (Fig. 3), which is extensively expressed in the nervous system (see Table 1). In sensory neurons, expressions of PRLR-L and PRLR-S seldom overlap. 40 In the CNS, PRLR-L, and PRLR-S expression overlaps are common. 48,49 In such circumstances, it is not clear which cellular mechanisms are responsible for separating the effects of PRLR-L and ...
Context 14
... PRL (0.01-1ug/ml) regulation of hypothalamic neuroendocrine dopaminergic (NEDA) neurons demonstrated that PRL rapidly induces synthesis of catecholamine via protein kinase A (PKA) and C (PKC), but not Ca 2+ -dependent calmodulin kinase-II (CaMKII) pathways. 77 PRL application also led to a PKCdependent activation of ERK1/2 within the MAPK pathway (Fig. 3). 77 Interestingly, PRL-activated transcription does not involve PKA, PKC, CaMKII, or ERK1/2 77 . The role of PRLtriggered rapid signaling pathways in neurons was further studied in TRPV1 sensitization. Inhibition of several kinase pathways demonstrated that the transient actions of PRL on TRPV1 activities in sensory neurons are ...
Context 15
... PRL-activated transcription does not involve PKA, PKC, CaMKII, or ERK1/2 77 . The role of PRLtriggered rapid signaling pathways in neurons was further studied in TRPV1 sensitization. Inhibition of several kinase pathways demonstrated that the transient actions of PRL on TRPV1 activities in sensory neurons are directed by PI3-kinase or PKC (Fig. 3). 40 PKA and Src-kinase inhibitors however failed to affect TRPV1 activity enhancement by PRL. 40 Detailed investigation showed that the main PKC isoform involved in mediating PRL effects on TRPV1 in sensory neurons is PKCε 40 . However, it is not clear whether the PKC pathway is downstream of the PI3-kinase pathway (Fig. 3). Rapid ...
Context 16
... by PI3-kinase or PKC (Fig. 3). 40 PKA and Src-kinase inhibitors however failed to affect TRPV1 activity enhancement by PRL. 40 Detailed investigation showed that the main PKC isoform involved in mediating PRL effects on TRPV1 in sensory neurons is PKCε 40 . However, it is not clear whether the PKC pathway is downstream of the PI3-kinase pathway (Fig. 3). Rapid induction of PI3-kinase by PRL in neurons of the CNS has been reported, and includes the suppression of BK-type Ca 2+ -dependent K + -currents in TIDA neurons by way of the PI3-kinase pathway (Fig. 3). 58 In summary, it appears that PRL activates two principally distinct signaling pathways in neurons. The first involves PRLR-L ...
Context 17
... effects on TRPV1 in sensory neurons is PKCε 40 . However, it is not clear whether the PKC pathway is downstream of the PI3-kinase pathway (Fig. 3). Rapid induction of PI3-kinase by PRL in neurons of the CNS has been reported, and includes the suppression of BK-type Ca 2+ -dependent K + -currents in TIDA neurons by way of the PI3-kinase pathway (Fig. 3). 58 In summary, it appears that PRL activates two principally distinct signaling pathways in neurons. The first involves PRLR-L and the phosphorylation of STAT5, leading to long-lasting effects based on transcription activation (Fig. 3). The second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, ...
Context 18
... the suppression of BK-type Ca 2+ -dependent K + -currents in TIDA neurons by way of the PI3-kinase pathway (Fig. 3). 58 In summary, it appears that PRL activates two principally distinct signaling pathways in neurons. The first involves PRLR-L and the phosphorylation of STAT5, leading to long-lasting effects based on transcription activation (Fig. 3). The second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, with subsequent modulation of neuronal channels, excitability and neurotransmission (Fig. 3). The schematic presented in Figure 3 is a simplified pathway, but underscores the primary signaling events following activation of neurons by ...
Context 19
... signaling pathways in neurons. The first involves PRLR-L and the phosphorylation of STAT5, leading to long-lasting effects based on transcription activation (Fig. 3). The second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, with subsequent modulation of neuronal channels, excitability and neurotransmission (Fig. 3). The schematic presented in Figure 3 is a simplified pathway, but underscores the primary signaling events following activation of neurons by endogenous or exogenous PRL. PI3-kinase, PKC and ERK1/2 can regulate a variety of ligand-and voltage-gated channels in neurons. Thus, PKC activation results in production of diacylglycerol (DAG), ...
Context 20
... second pathway recruits PRLR-S, leading to rapid activation of PI3-kinase, ERK1/2 and/or PKC, with subsequent modulation of neuronal channels, excitability and neurotransmission (Fig. 3). The schematic presented in Figure 3 is a simplified pathway, but underscores the primary signaling events following activation of neurons by endogenous or exogenous PRL. PI3-kinase, PKC and ERK1/2 can regulate a variety of ligand-and voltage-gated channels in neurons. ...
Similar publications
Many clinical and preclinical studies report an increased prevalence and severity of chronic pain among females. Here, we identify a sex-hormone-controlled target and mechanism that regulates dimorphic pain responses. Prolactin (PRL), which is involved in many physiologic functions, induces female-specific hyperalgesia. A PRL receptor (Prlr) antago...
Citations
... Several studies on hyperprolactinemia under conditions of hypoxemia have been reported [17][18][19]. In addition, other pathological conditions that have been reported to be associated with elevated PRL levels include physiological and physical stress (trauma), such as burns, surgery, and post-traumatic stress disorder [20]. In our previous study, we reported that PRL levels were increased in the cerebrospinal fluid (CSF) during acute systemic hypoxia due to asphyxia, and PRL was transported from the blood to the CSF via the choroid plexus under hypoxia [21]. ...
The levels and potential role of prolactin (PRL) in the brain under conditions of acute systemic hypoxia were examined, focusing on the accumulation of PRL in cerebrospinal fluid (CSF) and its effects on neuronal activity and injury. The amount of PRL in the brain was investigated using brain tissues from forensic autopsy cases. We counted the number of neurites that formed in human primary neurons (HNs) after the addition of PRL. Furthermore, HNs supplemented with PRL or triiodothyronine (T3) were exposed to hypoxic conditions, and the dead cells were counted. The results showed correlations between brain PRL and CSF PRL levels. Additionally, PRL accumulation in the brain was observed in cases of asphyxia. In vitro experimental findings indicated increased neurite formation in the HNs treated with PRL. Moreover, both PRL and T3 demonstrated neuroprotective effects against hypoxia-induced neuronal cell death, with PRL showing stronger neuroprotective potential than T3. These results suggest that PRL accumulates in the brain during hypoxia, potentially influences neuronal activity, and exhibits neuroprotective properties against hypoxia-induced neuronal injury.
... [16,27,29]. They are composed of three domains: extracellular, with two regions, designated S1 and S2 (or D1 and D2) that together form the ligand binding site; transmembrane, which is identical in both species; and intracellular or cytoplasmic, of variable length and composition [20,22,27,28]. PRLRs are mainly related to the activation of the JAK2-STAT5 signaling pathway but can initiate other signaling cascades, in addition to being ubiquitously expressed in various tissues [16,24,29]. ...
... Multiple PRLR isoforms resulting from alternative splicing of the primary mRNA transcript have been identified in rodents and humans [22,29,31]. These isoforms have identical extracellular and transmembrane domains, only differing in length and sequence in the intracellular domains [20,32]. Three different isoforms of PRLRs have been identified in rats: short (PRLR-S), intermediate (PRLR-I), and long (PRLR-L) [16,22], while a soluble isoform has been described in humans. ...
Prolactin (PRL) is a peptide and pleiotropic hormone with more than 300 associated functions such as maternal behavior, lactation, osmoregulation, angiogenesis, and the immune system. It is associated with several functions in the brain, including lactation, cognition and memory, maternal behavior, and neurogenesis. PRL reportedly plays an important role in neuroprotection against excitotoxicity caused by glutamate (Glu) and kainic acid (KA) damage in vitro and in vivo models. However, the molecular mechanisms involved in the neuroprotective effects of PRL are unclear. Despite this, data suggest the involvement of PI3K/AKT, and GSK3β/NF-κB signaling pathways, which are involved in neuroprotection. In addition, PRL inhibits Glu- and KA-induced increase by intracellular Ca2+ concentration, leading to neuronal survival. We also discuss current knowledge on the role of PRL in neurodegenerative diseases. New avenues of research into the protective mechanisms of PRL and its potential therapeutic effects on the brain under pathological and physiological conditions are needed.
... We previously found alterations to plasma levels of the hormones prolactin and oxytocin at early stages of FEP, resulting in higher prolactin and lower oxytocin levels compared to healthy controls (Hidalgo-Figueroa et al., 2022). Prolactin plays a notable role in lactation and it is involved in several activities controlled by the brain, such as energy balance, anxiety, stress regulation, food intake and maternal behaviour (Patil et al., 2014;Delgado-Alvarado et al., 2019). Antipsychotic medication usually elevates this hormone in patients with schizophrenia, yet unmedicated patients also have higher prolactin levels than healthy control individuals (Garcia-Rizo et al., 2012;Riecher-Rössler et al., 2013;Petrikis et al., 2016;Delgado-Alvarado et al., 2019;Pisk et al., 2019;Studerus et al., 2021). ...
Background:
The clinical debut of schizophrenia is frequently a first episode of psychosis (FEP). As such, there is considerable interest in identifying associations between biological markers and clinical or cognitive characteristics that help predict the progression and outcome of FEP patients. Previous studies showed that high prolactin, low oxytocin and high homocysteine are factors associated with FEP 6 months after diagnosis, at which point plasma levels were correlated with some clinical and cognitive characteristics.
Methods:
We re-examined 75 patients 12 months after diagnosis to measure the evolution of these molecules and to assess their association with clinical features.
Results:
At follow-up, FEP patients had lower prolactin levels than at baseline, and patients treated with risperidone or paliperidone had higher prolactin levels than patients who received other antipsychotic agents. By contrast, no changes in oxytocin and homocysteine plasma levels were observed between the baseline and follow-up. In terms of clinical features, we found that plasma prolactin and homocysteine levels were correlated with the severity of the psychotic symptoms in male FEP patients, suggesting that they might be factors associated with psychotic symptomatology but only in men. Together with oxytocin, these molecules may also be related to sustained attention, verbal ability and working memory cognitive domains in FEP patients.
Conclusion:
This study suggests that focusing on prolactin, oxytocin and homocysteine at a FEP may help select adequate pharmacological treatments and develop new tools to improve the outcome of these patients, where sex should also be borne in mind.
... The increased neuronal excitability in nociceptive pathways can be regulated by several factors including steroids and pituitary-derived hormones such as PRL [14,94,[97][98][99]. In this respect, PRL is capable of inducing action potential firing in sensory nerves, which can be regulated via the activation of PRLR [14,99]. ...
... The increased neuronal excitability in nociceptive pathways can be regulated by several factors including steroids and pituitary-derived hormones such as PRL [14,94,[97][98][99]. In this respect, PRL is capable of inducing action potential firing in sensory nerves, which can be regulated via the activation of PRLR [14,99]. Nevertheless, although PRLR is expressed in both males and females, PRL-induced neuronal excitability in inflammatory pain was detected only in dorsal root ganglion neurons of female mice [14,99], which may be due to a higher expression of the PRLR in females. ...
... In this respect, PRL is capable of inducing action potential firing in sensory nerves, which can be regulated via the activation of PRLR [14,99]. Nevertheless, although PRLR is expressed in both males and females, PRL-induced neuronal excitability in inflammatory pain was detected only in dorsal root ganglion neurons of female mice [14,99], which may be due to a higher expression of the PRLR in females. Therefore, it seems that PRL-regulated sensory neuronal excitability is a female-specific mechanism which also depends on estrogen [14]. ...
Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.
... PRLR encodes a receptor belonging to a type I cytokine receptor superfamily that binds prolactin, which is an anterior pituitary hormone. Prolactin and its receptor (PRLR) can regulate a wide variety of physiological functions in the nervous system [45]. Additionally, prolactin can suppress the expression of inducible NO synthase (NOS) induced by proinflammatory cytokines [46]. ...
Background
Cold-induced vasodilation (CIVD) occurs after blood vessels in the skin are constricted due to local cold exposure. Although many CIVD studies have been conducted, the underlying molecular mechanisms are yet to be clarified. Therefore, we explored genetic variants associated with CIVD response using the largest-scale dataset reported to date in a CIVD study involving wavelet analysis; thus, the findings improve our understanding of the molecular mechanisms that regulate the CIVD response.
Methods
We performed wavelet analysis of three skin blood flow signals [endothelial nitric oxide (eNO)-independent, eNO-dependent, and neurogenic activities] during finger cold-water immersion at 5 °C in 94 Japanese young adults. Additionally, we conducted genome-wide association studies of CIVD using saliva samples collected from the participants.
Results
We found that the mean wavelet amplitudes of eNO-independent and neurogenic activities significantly increased and decreased prior to CIVD, respectively. Our results also implied that as many as ~ 10% of the Japanese subjects did not show an apparent CIVD response. Our genome-wide association studies of CIVD using ~ 4,040,000 imputed data found no apparent CIVD-related genetic variants; however, we identified 10 genetic variants, including 2 functional genes ( COL4A2 and PRLR ) that are associated with notable blunted eNO-independent and neurogenic activity responses in individuals without CIVD response during local cold exposure.
Conclusions
Our findings indicate that individuals without CIVD response differentiated by genotypes with COL4A2 and PRLR genetic variants exhibited notable blunted eNO-independent and neurogenic activity responses during local cold exposure.
... Hyperprolactinemia in patients with prolactinomas may affect brain function directly or indirectly 18 . The direct effect involves prolactin receptors that are widely distributed in the neural tissue, meaning that prolactin overproduction can affect neurotransmission, functional circuits, and neuronal signaling pathways across the entire brain 19 . The indirect effect results from an imbalance of other hormones and neurotransmitters. ...
Prolactinomas (prolactin-secreting adenomas) are the most common type of hormone-secreting pituitary tumor. Mounting evidence indicates that excess prolactin impairs cognitive function, but specific assessments of attention in patients with prolactinomas are lacking. Case–control study gathered 54 participants—27 patients with prolactinoma and 27 healthy controls. Neuropsychological assessment included a comprehensive set of diagnostic methods for the evaluation of attention and working memory. Patients showed slower information processing, expressed as a longer working time on the d2 Test of Attention and Color Trails Test (CTT-2), and lower attention-switching shown in the CTT-2 and in two subtests of the Tests of Everyday Attention (Visual Elevator), and Telephone Search While Counting. Working memory disturbances were observed in Digit Span and Symbol Span tests. A level of prolactin correlated negatively with scores in some of the neuropsychological tests measuring attentional switching (Visual Elevator), spatial screening and working memory (CTT-2), spatial working memory (Symbol Span) and auditory-verbal working memory (Digit Span backwards). There were no significant correlations between cognitive performance and tumor size. In conclusion, patients with prolactinoma suffer from impaired cognitive functions, including attention and working memory. Comprehensive neuropsychological assessment should be a permanent element of the diagnostics of this group of patients.
... Prolactin is a hormone mainly synthesized in the anterior pituitary gland, with a notable role in lactation (Delgado-Alvarado et al., 2019). In addition, prolactin is involved in several central nervous system functions, such as the regulation of stress, energy balance, anxiety, neurogenesis, food intake, and maternal behavior (Patil et al., 2014). Patients with schizophrenia frequently have elevated levels of prolactin as a consequence of pharmacological treatment, although an increase in prolactin has also been demonstrated in untreated psychiatric patients (Garcia-Rizo et al., 2012;Riecher-Rössler et al., 2013;Petrikis et al., 2016;Delgado-Alvarado et al., 2019;Pisk et al., 2019;Studerus et al., 2021). ...
Background
Around 3% of the population suffers a first episode of psychosis (FEP) and a high percentage of these patients subsequently relapse. As the clinical course following a FEP is hard to predict, it is of interest to identify cognitive and biological markers that will help improve the diagnosis, treatment and outcome of such events, and to define new therapeutic targets. Here we analyzed the plasma oxytocin and prolactin levels during a FEP, assessing their correlation with clinical and cognitive features.
Methods
The oxytocin and prolactin in plasma was measured in 120 FEP patients and 106 healthy controls, all of whom were subjected to a clinical and neuropsychological assessment. Most patients were under antipsychotics. Statistical analyses aimed to identify factors associated with the FEP and to search for associations between the variables.
Results
FEP patients had less oxytocin, more prolactin, a poor premorbid-IQ and they performed worse in sustained attention. Male patients with higher prolactin levels experienced more severe psychotic symptoms and required higher doses of antipsychotics. Low oxytocin was associated with poor sustained attention in women, whereas low oxytocin and high prolactin in men correlated with better performance in sustained attention.
Conclusion
Low oxytocin, high prolactin, and poor premorbid-IQ and sustained attention are factors associated with a FEP, representing potential therapeutic targets in these patients. These biological factors and cognitive domains might play an important role during a FEP, which could help us to develop new strategies that improve the outcomes of this disorder and that should perhaps be gender specific.
... In humans, patients with adenomyosis frequently exhibit hyperprolactinemia [113,133], but one less appreciated result is that the elevated levels of PRL can cause increased pain by promoting nociceptor sensitization through the short isoform of PRLR (RPLR-S) [134][135][136][137][138], the expression of which is also found to be higher in the bovine uterus with adenomyosis [139] and, we can speculate, in humans as well. DRD2 agonists have been shown to suppress PRL-induced adenomyosis and also have therapeutic potential for reducing pain and treating adenomyosis, likely through the promotion of the long isoform of PRLR (PRLR-L) and the inhibition of angiogenesis by DRD2 [140][141][142][143]. ...
Background:
Adenomyosis is a common gynecological disorder traditionally viewed as "elusive". Several excellent review papers have been published fairly recently on its pathogenesis, and several theories have been proposed. However, the falsifiability, explanatory power, and predictivity of these theories are often overlooked. Since adenomyosis can occur spontaneously in rodents and many other species, the animal models may help us unveil the pathogenesis of adenomyosis. This review critically tallies experimentally induced models published so far, with a particular focus on their relevance to epidemiological findings, their possible mechanisms of action, and their explanatory and predictive power.
Methods:
PubMed was exhaustively searched using the phrase "adenomyosis and animal model", "adenomyosis and experimental model", "adenomyosis and mouse", and "adenomyosis and rat", and the resultant papers were retrieved, carefully read, and the resultant information distilled. All the retrieved papers were then reviewed in a narrative manner.
Results:
Among all published animal models of adenomyosis, the mouse model of adenomyosis induced by endometrial-myometrial interface disruption (EMID) seems to satisfy the requirements of falsifiability and has the predictive capability and also Hill's causality criteria. Other theories only partially satisfy Hill's criteria of causality. In particular, animal models of adenomyosis induced by hyperestrogenism, hyperprolactinemia, or long-term exposure to progestogens without much epidemiological documentation and adenomyosis is usually not the exclusive uterine pathology consequent to those induction procedures. Regardless, uterine disruption appears to be a necessary but not sufficient condition for causing adenomyosis.
Conclusions:
EMID is, however, unlikely the sole cause for adenomyosis. Future studies, including animal studies, are warranted to understand how and why in utero and/or prenatal exposure to elevated levels of estrogen or estrogenic compounds increases the risk of developing adenomyosis in adulthood, to elucidate whether prolactin plays any role in its pathogenesis, and to identify sufficient condition(s) that cause adenomyosis.
... Another example is that of prolactin. When functioning normally, prolactin contributes towards the control of numerous biological circuits, including those underlying anxiety, neurogenesis, food intake, maternal behaviour, and pain [215]. However, alterations in its activity have been associated with pathology in both AD and PD (reviewed by Nguyen et al. [216]), the two most common neurodegenerative diseases. ...
... Prolactin Reported roles in neurogenesis and neuronal stem cell proliferation. Expressed on microglia and astrocytes with suggestive roles in inflammatory response [215]. ...
Despite recent leaps in modern medicine, progress in the treatment of neurological diseases remains slow. The near impermeable blood-brain barrier (BBB) that prevents the entry of therapeutics into the brain, and the complexity of neurological processes, limits the specificity of potential therapeutics. Moreover, a lack of etiological understanding and the irreversible nature of neurological conditions have resulted in low tolerability and high failure rates towards existing small molecule-based treatments. Neuropeptides, which are small proteinaceous molecules produced by the body, either in the nervous system or the peripheral organs, modulate neurological function. Although peptide-based therapeutics originated from the treatment of metabolic diseases in the 1920s, the adoption and development of peptide drugs for neurological conditions are relatively recent. In this review, we examine the natural roles of neuropeptides in the modulation of neurological function and the development of neurological disorders. Furthermore, we highlight the potential of these proteinaceous molecules in filling gaps in current therapeutics.
... PRL is released by pituitary and extrapituitary tissues during injuries and trauma (Freeman et al., 2000;Marano and Ben-Jonathan, 2014;Scotland et al., 2011). This release of PRL has sex-dependent effects on nociception and sensory neuron sensitization due to differential expression of PRLR in females versus male sensory neurons (Patil et al., 2019b;Patil et al., 2014;Patil et al., 2013). As a result of PRL-induced transient sensitization of sensory neurons, ablation of PRLR on DRG neurons sex-dependently reduces hypersensitivity in acute pain models/conditions (Patil et al., 2019a). ...
Pain development and resolution patterns in many diseases are sex-dependent. This study aimed to develop pain models with sex-dependent resolution trajectories, and identify factors linked to resolution of pain in females and males. Using different intra-plantar (i.pl.) treatment protocols with prolactin (PRL), we established models with distinct, sex-dependent patterns for development and resolution of pain. An acute PRL-evoked pain trajectory, in which hypersensitivity is fully resolved within 1 day, showed substantial transcriptional changes after pain-resolution in female and male hindpaws and in the dorsal root ganglia (DRG). This finding supports the notion that pain resolution is an active process. Prolonged treatment with PRL high dose (1μg) evoked mechanical hypersensitivity that resolved within 5-7 days in mice of both sexes and exhibited a pro-inflammatory transcriptional response in the hindpaw, but not DRG, at the time point preceding resolution. Flow cytometry analysis linked pro-inflammatory responses in female hindpaws to macrophages/monocytes, especially CD11b⁺/CD64⁺/MHCII⁺ cell accumulation. Prolonged low dose PRL (0.1μg) treatment caused non-resolving mechanical hypersensitivity only in females. This effect was independent of sensory neuronal PRLR and was associated with a lack of immune response in the hindpaw, although many genes underlying tissue damage were affected. We conclude that different i.pl. PRL treatment protocols generates distinct, sex-specific pain hypersensitivity resolution patterns. PRL-induced pain resolution is preceded by a pro-inflammatory macrophage/monocyte-associated response in the hindpaws of mice of both sexes. On the other hand, the absence of a peripheral inflammatory response creates a permissive condition for PRL-induced pain persistency in females.
