Substance P/Neurokinin 1 and Trigeminal System: A Possible Link to the Pathogenesis in Sudden Perinatal Deaths

Abstract

Sudden demise of a healthy fetus or a neonate is a very tragic episode in the life of parents. These deaths have been a mystery since ages but still remain unexplained. This review proposes the involvement of trigeminal nerve, neurotransmitter substance P (SP), and its receptor neurokinin 1 (NK-1R) in regulation of cardiorespiratory control in fetuses and newborns. Anomalies and immaturity of neuroregulatory systems such as trigeminal system in medulla oblongata of brainstem may provide a possible mechanism of sudden perinatal deaths. Vulnerable infants are born with respiratory center immaturity which in combination with any stressor such as cold, hypoxia, and smoking may lead to cessation of breathing and ventilatory response. SP/NK-1R may be involved in regulating the ventilatory control in neonates while it is decreased in fetal and adult life in humans, and any alterations from these may lead to irreversible sleep apnea and fatal breathing, ultimately sudden death. This review summarizes the studies performed to highlight the expression of SP or NK-1R in sudden perinatal deaths and proposes the involvement of trigeminal ganglion along with its nerve and SP/NK-1R expression alteration as one of the possible pathophysiological underlying mechanism. However, further studies are required to explore the role of SP, NK-1R, and trigeminal system in the pathogenesis of sudden infant deaths, sudden intrauterine deaths, stillbirths, and sudden deaths later in human life.

Elevated Neurokinin 1-Receptor Expression in uterine products of conception is associated with first trimester Miscarriages

“…SP-IR has an opposite correlation with NK-1R protein expression in pregnant and uterus after birth [29]. It correlates with our own previous study [30], in which it was proposed, based on our experimental work on sudden infant death syndrome, sudden fetal death victims and controls, [31] that SP expression is normally low in healthy fetuses but higher in neonates as compared to controls and if vice versa, it may lead to sudden death. Furthermore, it was proposed that the expression of SP is variable, depending on the developmental stage.…”

“…Furthermore, it was proposed that the expression of SP is variable, depending on the developmental stage. It is lower in adults and if increased it may lead to death [30]. The possible reason is that SP is involved in cardiorespiratory control centers of the brain and has many important functions [32,33].…”

Towards Better Understanding of the Pathogenesis of Neuronal Respiratory Network in Sudden Perinatal Death

“…The cranial nerves transmit pain stimuli from peripheral regions to the STrN (59). A reduced SP expression levels in the fibers of STrN in SIDS victims and higher levels in SIUDS victims were observed (20, 48). …”

“…More recently, some new theories have been proposed, and it was highlighted that infant gut microbiome may modulate the brainstem serotonergic system and may serve as a new possible risk factor for causing SIDS (19). Latest theories like SIDS-critical diaphragm failure hypothesis suggest that the critical diaphragm failure during pregnancy may end up in SIDS by cessation of breathing (15), whereas substance P–neurokinin 1 hypothesis suggests a possible involvement of this tachykinin peptide in sudden perinatal deaths by modulating the cardiorespiratory control (20). …”

Prognostic significance of Substance P/ Neurokinin 1 receptor and its association with hormonal receptors in breast carcinoma

“…Previously, we had demonstrated the immunohistochemical expression of SP in the sudden fetal and infant deaths and neuropathology [33][34][35][36]. We also established SP expression in Oral Squamous Cell Carcinoma (OSCC), where SP strong expression was found to be related with the progression of OSCC and aided as a diagnostic marker [22].…”