Effects Of Combined Treatment Of InterAlpha Inhibitor Proteins (IAIPs) With Hypothermia in Neonatal Rats Exposed With Hypoxic-ischemic (HI) Brain Injury

BACKGROUND:

Hypoxic-ischemic (HI) brain injury is one of the most common neurological problems observed in infants. Hypothermia is the only approved therapy for neonatal HI encephalopathy. This therapy is only partially protective, cannot be used in preterm infants, and has a narrow therapeutic window after birth. 

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Therefore, additional adjunctive therapies are urgently required. IAIPs are naturally plasma-derived proteins. We have previously shown that IAIP alone reduces cortical neuronal cell death, improves behavior outcomes, and attenuates brain volume loss in neonatal HI rats (Chen et al., 2019; Schuffels et al., 2020). However, the therapeutic effects of the combined treatment of IAIPs with hypothermia have not been previously established in neonatal rats. 

PURPOSE: 

To examine the effects of combined treatment of IAIPs with hypothermia on brain infarct volumes after exposure to HI insults in male and female neonatal rats. 

METHODOLOGY: 

The Rice-Vannucci method was used to induce HI, e.g. unilateral carotid artery ligation followed by hypoxic exposure to 90 min of 8% O2 at postnatal (P) day 7. After recovery of HI, the pups were treated either with normothermia (rectal temperature 36°C) or hypothermia (rectal temperature 30°C) for 3 h. 

The rats were randomly assigned to 6 groups: (1) normothermia+Placebo (PL, Sham); (2) normothermia+HIPL; (3) normothermia+HI-IAIP; (4) hypothermia (rectal temperature 30)+Sham; (5) hypothermia+HI-PL; and (6) hypothermia+HI-IAIP. HI, animals received PL (phosphate buffered saline) or human plasma-derived IAIPs (30 mg/ kg) intraperitoneally (i.p.) at 0, 24, and 48 h after HI. At P14, brains were collected for infarct volume measurement (Fig. A and B). 

RESULTS: 

Under normothermia, treatment with IAIPs significantly attenuated brain volume loss in the cohort (male+female), male and female neonatal rats (P<0.05, Fig. C). Compared to the normothermia+HI-PL group, the combined treatment of IAIPs with hypothermia attenuated brain volume loss in cohort and females (P<0.05), but not in males. In females, the brain volume loss in hypothermia+HI-IAIP groups was reduced compared to the normothermia+HI-IAIP, suggesting that the combined treatment of IAIPs with hypothermia enhanced IAIP neuroprotection in HI brain injury. No difference between the hypothermia+HI-PL and hypothermia+HI-IAIP groups was observed. 

CONCLUSIONS: 

The combined treatment of IAIPs with hypothermia attenuates brain volume loss in the cohort and female neonatal rats after exposure to HI. Although IAIPs could be an additional adjunctive therapy for infants that currently receive therapeutic hypothermia, the optimal dose, and therapeutic windows remain to be determined.

How does cistanche treat brain cell damage?

Cistanche has been traditionally used in Chinese medicine to improve brain function and treat neurological disorders. Studies have suggested that cistanche may help to protect brain cells by reducing inflammation and oxidative stress in the brain, thus improving neuronal survival. One study published in the Journal of Traditional and Complementary Medicine found that cistanche extract helped to protect brain cells against damage caused by oxygen and glucose deprivation. 

The researchers concluded that cistanche extract could be a potential therapeutic agent for the treatment of neurodegenerative diseases. Another study published in the Journal of Alzheimer's Disease found that cistanche polysaccharides, which are the main active compounds in cistanche, were able to protect brain cells from toxicity and prevent cognitive impairment in a mouse model of Alzheimer's disease.

References:

-Chen, X., et al., 2019. Neuroprotective effects of inter-alpha inhibitor proteins after hypoxic-ischemic brain injury in neonatal rats. Exp Neurol. 317, 244- 259. 

- Schuffels, S., et al., 2020. Effects of inter-alpha inhibitor proteins on brain injury after exposure of neonatal rats to severe hypoxia-ischemia. Exp Neurol. 334, 113442.

- Zou Y, Lu Y, Wei D. Neuroprotective effects of the aqueous extract of Cistanche deserticola Y.C. Ma against oxidative stress-induced neuronal death through the PKCε/Akt/CREB signaling pathway. J Ethnopharmacol. 2016 Aug 2;189:169-78. doi: 10.1016/j.jep.2016.04.037. Epub 2016 Apr 25. PMID: 27125471.

- Zhang W, Wei N, Su F, et al. Cistanche deserticola polysaccharides rejuvenate LPS-induced acute aging in mice. Age (Dordr). 2014;36(3):9683. doi:10.1007/s11357-014-9683-1.

- Li Y, Jin F, Li X, et al. Polysaccharide of Cistanche deserticola attenuates oxidative stress and hippocampal damage in a rat model of Alzheimer’s disease. J Alzheimer’s Dis. 2015;43(3):977-988. doi:10.3233/JAD-132416.