Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sudden Infant Death Syndrome: A Potential Model for Investigation
Abstract
:1. Introduction
2. In Vivo Data
2.1. Knock Out Mouse Models
2.1.1. PACAP Knock Out Mice
2.1.2. PAC1R Knock Out Mice
2.2. Other Observations
3. Human Data
4. Discussion
- PACAP deficiency was found to be associated with impaired lipid and carbohydrate metabolism and an impaired response to metabolic stress [34,36]. For years, it has been known that metabolic diseases can occasionally manifest as SIDS, and human studies indicate that metabolic disorders might be responsible for 1% to 2% of SIDS cases [68,69]. These conditions can lead to severe cardiac failure, shock, cardiac arrest, or acute metabolic crises. Among metabolic disorders, fatty acid oxidation disorders are the most common culprits behind SIDS, and they can often appear with minimal or no preceding clinical symptoms [70,71]. These fatty acid oxidation disorders may be associated with lipid accumulation in various tissues, including skeletal muscle and the liver. Regarding carbohydrate metabolism, genetic deficiencies in the hepatic glucose-6-phosphatase system can lead to fasting hypoglycaemia and, hence, the risk of SIDS. Low hepatic glucose-6-phosphatase catalytic subunit 1 (G6PC1) activities have been previously observed in some full-term SIDS infants. In preterm SIDS infants, there is an indication of disrupted development, as failures in the postnatal activation of G6PC1 expression have been reported [72,73]. The significant downregulation of proteins linked to oxidative stress and antioxidant defence in PACAP-knockout mice [40] underscores that PACAP deficiency influences homeostasis and metabolic activity across multiple domains.
- Thermoregulatory disturbances have been noted in PACAP-deficient mice, where the absence of endogenous PACAP has led to insufficient heat production, primarily due to inadequate norepinephrine stimulation of brown adipose tissue during prolonged but mild cold stress [35]. This altered thermogenesis of PACAP-null mice has also been confirmed by another study [54]. They display hypometabolism and hypothermia under restrained conditions, partially compensated by increased locomotor activity under unrestrained conditions. PACAP is known to inhibit GABAergic neurons in the hypothalamic preoptic area and median preoptic nucleus, which leads to increased body temperature. The absence of this inhibitory mechanism could be the reason behind the decreased temperature and deficient thermoregulation in mice lacking PACAP, although the involvement of other brain structures has also been suggested in this mechanism [54]. During infancy, a hypothesis suggests that brown adipose tissue could play a role in the onset of sudden infant death syndrome (SIDS). This hypothesis is based on the idea that thermal stresses and disrupted thermogenesis are factors in this condition. However, it is important to note that human studies have not confirmed this hypothesis [74].
- In the PACAP knockout mice, there was also evidence of impaired autonomic responses to heat stress, characterized by reduced sympathetic responses. Specifically, the PACAP-null animals exhibited a significantly decreased respiratory rate, tidal volume, and minute ventilation during heat stress, along with slightly longer apnoea durations [41]. Infants are particularly vulnerable to heat stress because their temperature regulation mechanisms are still developing. The interplay between thermal stress and the body’s protective homeostatic responses can lead to potentially life-threatening situations, especially during sleep. It is known that respiration is highly influenced by thermoregulation, so thermal stress can have significant effects on the characteristics of respiratory control. Exposure to heat can negatively affect the autonomic nervous system, potentially disrupting the drive for cardiorespiratory function and hindering the ability to awaken when a vital system is compromised [75]. A study involving sleeping preterm neonates observed that even small thermal loads are associated with reduced overall heart rate variability [76]. Autonomic control also appears to be impaired in SIDS victims [77,78]. Anatomical abnormalities within the intermediolateral nucleus of the spinal cord have been documented in 60% of SIDS cases [79]. This nucleus houses PACAPergic preganglionic sympathetic neurons, which are crucial for regulating cardiorespiratory responses to heat and various physiological stressors. Notably, it is susceptible to pathological changes when exposed to maternal cigarette smoke, a significant risk factor associated with SIDS.
- In mice, PAC1R deficiency has been associated with pulmonary hypertension, which can lead to right heart failure and subsequent death within the second postnatal week [42]. Human data regarding abnormalities in pulmonary vessels observed in cases of SIDS are limited and somewhat controversial. Early observations noted increased muscularity in the pulmonary circulation of SIDS victims [80]. Bradley and colleagues reported a case of SIDS where pulmonary artery thickening and associated pulmonary hypertension played a critical role in the death of a 23-day-old infant [81]. Another study found that the mean relative medial thickness of the alveolar wall arteries did not differ between SIDS cases and age-matched control cases. However, within the SIDS group, the thickest alveolar wall arteries were significantly more likely to be males and premature births [82].
- The PACAP-null mice exhibited higher neonatal mortality primarily due to defects in respiratory control. They displayed reduced baseline minute ventilation and impaired ventilatory responses to hypercapnia and hypoxia. When exposed to hypothermia, these mice experienced prolonged apnoea, and, notably, the P7 PACAP-null mice had respiratory arrest in response to hypoxia [38,39]. PAC1R deficiency also led to impaired cardiorespiratory responses to both hypoxia and hypercapnia. This included blunted respiratory rate and minute ventilation responses to both hypoxia and hypercapnia, along with impaired post-hypoxic and post-hypercapnic cardiorespiratory recovery [43,44]. An investigation into the impact of acute and repeated intermittent hypercapnic hypoxia, simulating rebreathing in the prone position, on PACAP and PAC1R protein expression revealed that intermittent hypercapnic hypoxia led to a decrease in both PACAP and PAC1R expression in the brainstem nuclei responsible for respiratory regulation [45]. Another study indicated that precisely timed PACAP expression in the pre-Bötzinger complex and the RTN/parafacial respiratory group plays a crucial role in providing additional respiratory drive immediately after birth and supporting breathing during a particularly vulnerable phase of life [47]. These findings align with human data since the central nervous system in specific brainstem regions within the ventrolateral medulla controls the cardiorespiratory system. It is worth noting that each of these brainstem regions has specialized functions in regulating breathing and heartbeat: the pre-Bötzinger complex governs inspiration, the post-inspiratory complex controls post-inspiratory activity, and a subset of the parafacial respiratory group manages active expiration [83]. TH immunoreactive catecholaminergic neurons within the ventrolateral medulla oblongata display delayed dendritic development in SIDS individuals [84]. Furthermore, TH immunopositivity experiences a significant decrease in the DMNV and the area reticularis superficialis ventrolateralis of the medulla oblongata in SIDS cases [85].
- Nicotine exposure resulted in decreased PAC1R expression in piglets in the DMNV, while in mice, an increase in PAC1R expression was observed in NTS, CUN, NSTT, and ION [45,46]. Pre- and/or postnatal exposure to cigarette smoke is a factor that increases infant vulnerability to SIDS, with more than 40 studies showing a positive association and risk ratios ranging from 0.7 to 4.85. This heightened risk of SIDS is likely attributed to the effects of nicotine exposure on autonomic control and arousal, affecting, among others, the same brainstem nuclei [86].
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Condition(s) | Observations | Reference | Translational Value | |
PACAP knock out mice | general |
| [29] | corresponds with epidemiological data related to human SIDS |
metabolism (lipid and carbohydrate) |
| [34] | can be identified in specific subsets of human SIDS cases. | |
thermal regulation (cold stress) |
| [35] | not proved in human SIDS cases | |
metabolism (carbohydrate) |
| [36] | can be identified in specific subsets of human SIDS cases. | |
general |
| [37] | no human data | |
respiratory and thermal (cold stress) regulation |
| [38] | corresponds/similarities with data related to human SIDS | |
respiratory regulation |
| [39] | corresponds/similarities with data related to human SIDS | |
general |
| [40] | no human data | |
respiratory and thermal (heat stress) regulation |
| [41] | corresponds/similarities with data related to human SIDS | |
PAC1R knock out mice | general |
| [30] | corresponds with epidemiological data related to human SIDS |
general |
| [42] | controversial data in human studies | |
cardiorespiratory regulation |
| [43] | corresponds/similarities with data related to human SIDS | |
cardiorespiratory regulation |
| [44] | corresponds/similarities with data related to human SIDS | |
Other in vivo data | respiratory regulation (prone position, nicotine exposure)—piglet |
| [45] | corresponds/similarities with data related to human SIDS |
respiratory regulation (cigarette smoke exposure)—mice |
| [46] | corresponds/similarities with data related to human SIDS | |
respiratory regulation (transgenic mice and viral techniques) |
| [47] | corresponds/similarities with data related to human SIDS | |
Human data | genetic study |
| [48] | - |
genetic study |
| [49] | - | |
immunohistochemical study |
| [50] | - |
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Tóth, D.; Simon, G.; Reglődi, D. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sudden Infant Death Syndrome: A Potential Model for Investigation. Int. J. Mol. Sci. 2023, 24, 15063. https://doi.org/10.3390/ijms242015063
Tóth D, Simon G, Reglődi D. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sudden Infant Death Syndrome: A Potential Model for Investigation. International Journal of Molecular Sciences. 2023; 24(20):15063. https://doi.org/10.3390/ijms242015063
Chicago/Turabian StyleTóth, Dénes, Gábor Simon, and Dóra Reglődi. 2023. "Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) and Sudden Infant Death Syndrome: A Potential Model for Investigation" International Journal of Molecular Sciences 24, no. 20: 15063. https://doi.org/10.3390/ijms242015063