Table 2.
Study characteristics endogenous pathway studies, relevant findings, and methodological quality.
| References | Design | Population; no. | Technique | Relevant findings | Methodological Quality |
|---|---|---|---|---|---|
| NMDA/MAPK | |||||
| Dang et al. (31) | Prospective cohort | Piglets; N = 25 | H-MRS, DWI | The glutamate level in the basal ganglia underwent a “two-phase” change after HI: the first rise in glutamate after 0–6 h and second rise in glutamate after 24–30 h, due to reperfusion injury | High |
| Armstead et al. (32) | Prospective cohort | Rat pups; N = 65 | Closed Cranial Window | Treatment with Plasminogen Activator Inhibitor peptide EEIIMD prevents the impairment of vasodilator responses to hypercapnia and hypotension after HI, by upregulating p38 MAPK | High |
| Kiessling et al. (33) | Prospective cohort | Piglets; N = 90 | Closed Cranial Window | Inhibition of Urokinase Plasminogen Activator and Integrin prevents impairment of cerebrovasodilation after HI | Moderate |
| Armstead et al. (34) | Prospective cohort | Rat pups; N = 54 | Closed Cranial Window | Urokinase Plasminogen Activator impairs cerebrovasodilation through LRP and MAPK | High |
| Bari et al. (35) | Prospective cohort | Piglets; N = 53 | Closed Cranial Window | Kynurenine acid (KYNA) attenuates NMDA-induced pial artery dilatation; NMDA-induced arteriolar dilatation can be inhibited by KYNA | High |
| Philip et al. (36) | Prospective cohort | Newborn lambs; N = 42 | Closed Cranial Window | Protein thyrosine kinase and MAPK impairs NMDA-induced cerebrovasodilation by nociceptin/orphanin FQ activation | Moderate |
| Jagolino et al. (37) | Prospective cohort | Newborn lambs; N = 119 | Closed Cranial Window | Protein thyrosine kinase, MAPK and nociceptin/orphanin FQ impair hypercapnic cerebrovasodilation | Moderate |
| Perciaccante et al. (38) | Prospective cohort | Piglets; N = 60 | Intravital microscopy | (1) Hypothermia fails to preserve cerebral arteriolar dilatation to NMDA during and following ischemia; (2) Cerebral vascular responsiveness to an excitatory neurotransmitter is intact despite the reduced metabolic rate during hypothermia | Moderate |
| Armstead et al. (39) | Prospective cohort | Piglets; N = 42 | Closed Cranial Window | Nociceptin/Orphalin FQ and NMDA contribute to the impairment of hypotensive cerebrovasodilation | High |
| Taylor et al. (40) | Prospective cohort | Newborn lambs; N = 20 | Microinjection into the brain, Doppler imaging | (1) Local microinjection with NMDA increases both local and global CBF within minutes of injection; (2) Most marked increases in the right midbrain, diencephalon and temporal lobe; (3) Alterations in echotexture are primarily due to intracellular cytoplasmic changes and microscopic hemorrhage | High |
| NO | |||||
| Hsu et al. (14) | Prospective cohort | Postpartum day-7 rat pups; N = ? | Electron microscopy, doppler imaging | Microvascular damage post HI is contributed by neurnal NOS, nNOS underwent a “two-phase” change after HI: first rise in nNOS directly after the HI-event (swollen nucleoli, CBF↓); second rise 3 h after reoxygenation (overactive microglia, ↑CBF) | Moderate |
| Domoki et al. (41) | Prospective cohort | Piglets; N = 45 | Closed Cranial Window | NMDA-induced vasodilation is mediated by endothelium-independent nitric oxide release and activation of neuronal NOS positive neurons | Moderate |
| Dorrepaal et al. (42) | Prospective cohort | Newborn lambs; N = 16 | unknown | Inhibition of NOS by N-nitro-L-arginine (NLA) restores autoregulation of cerebral bloodflow, suggesting a role for nitric oxide-induced vasodilation in the impairment of autoregulation | Moderate |
| Wilderman et al. (15) | Prospective cohort | Piglets; N = ? | Closed Cranial Window | Neuronally derived NO contributes to hypoxic pial artery dilatation, through the formation of cGMP and the subsequent release of methionine enkephalin and leucine enkephalin | Moderate |
| Armstead et al. (16) | Prospective cohort | Piglets, N = ? | Closed Cranial Window | Contribution of Kca channel activation to hypoxic cerebrovasodilation is not mediated by NO/cGMP | Low |
| PROSTANOID | |||||
| Taniguchi et al. (17) | Prospective cohort | Rat pups, cell-specific knockout mouse pups; N = ? | unknown | Prostaglandin E2 EP4 receptor is cerebroprotective, it improves cerebral perfusion in both the contralateral and ipsilateral hypoxic-ischemic hemispheres | Moderate |
| Pourcyrous et al. (43) | Prospective cohort | Piglets; N = 15 | Radioactive microsphere CBF determination | (1) Brain stem bloodflow increases at 1min of asphyxia, is maintained at 5 min of asphyxia and increases more during reventilation than bloodflow to cerebrum and cerebellum; (2) Inhibition of prostanoid production with indomethacin does not limit vasoconstriction | High |
| Leffler et al. (26) | Prospective cohort | Piglets; N-12 | Radioactive microsphere CBF determination | The failure of hypercapnia to dilate pial arterioles after cerebral ischemia results from the inability of this stimulus to increase cerebral vasodilator prostanoid synthesis | Moderate |
| Leffler et al. (18) | Prospective cohort | Piglets; N = ? | Closed Cranial Window | (1) Prostanoid in cortical subarachnoid CSF increase during acute hypoxia combined with hypercapnia coincident with dilatation of the pial vessels; (2) Systemic indomethacin decreases pial artery dilatation in response to combined hypoxia and hypercapnia | Low |
| OTHER | |||||
| Parfenova et al. (44) | Prospective cohort | Piglets; N = 26 | Intravital microscopy, closed cranial window | CO, produced by astrocytes, has antioxidant effects (HO/CO and CORM-A1) and is cerebroprotective in neonatal asphyxia | High |
| Wilderman et al. (45) | Prospective cohort | Piglets, N = 65 | Closed Cranial Window | cAMP contributes to hypoxic pial artery dilatation; endogenous PACAP modulates cAMP-induced opioid release, thereby contributing to hypoxic pial artery dilatation | High |
| Rosenberg et al. (28) | Prospective cohort | Newborn lambs; N = 16 | Radioactive microsphere CBF determination | (1) Immediately after 5 min of asphyxia, increased CBF up to 60 min of reperfusion; (2) Damage by oxygen free radicals during postasphyxia cerebral reperfusion is important to the genesis of late postasphyxia bloodflow and oxygen metabolism abnormalities (treatment with activated polyethylene glycol catalase increases the CBF significantly 5 min postasphyxia) | Moderate |
cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CO, carbon monoxide; CORM-A1, CO-releasing molecule-A1; CSF, cerebrospinal fluid; DWI, diffusion-weighted imaging; HI, hypoxia ischemia; H-MRS, proton magnetic resonance imaging; HO, heme oxylase; Kca, calcium sensitive K-channel; LRP, lipoprotein-related protein; MAPK, mitogen-activated protein kinas; NMDA, n-methyl-d-aspartate, NO, nitric oxide, NOS, nitric oxide syntases; PACAP, pituitary adenylate cyclase-activating peptide.