ABSTRACT lateral ventricles, internal capsule, periventricular hemorrhages

ABSTRACT

The previous studies of intrauterine ischemic tissues obtained
from infant rat models treated with postnatal mechanic ventilation show that
transcription of SUR1 is upregulated. 1
The recent studies point that angiogenesis is induced by activation of MMP9
in intrauterine ischemia(IUI) observed in infant
rat models treated with postnatal mechanic ventilation and also LPC. 2
It provides us to think that SUR1 and MMP9 in a collaboration in intrauterine ischemia.
We will use inhibited and activated type of these proteins to understand this
relationship. It is known that glibenclamide has an inhibitory effect on SUR13
and TIMP is the inhibitor of MMP-9. 4 Thus, we will try to
understand is there any SUR1 effect on MMP9 upregulation and vice versa by
using inhibitors in this study.

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Keywords:
intrauterine ischemia(IUI), infant rat models, SUR1,
MMP9, glibenclamide

INTRODUCTION

Encephalopathy of prematurity(EP) is a term covers overall
brain dysfunction appearing in premature babies (have low birth weight) need to
mechanical ventilation in human. It is directly related with CNS injuries such
as ischemia, edema and especially hemorrhages. The infants had EP generally
have motor, cognitive, behavioral abnormalities in their entire life. Thus,
researches evaluated rat models that have prenatal intrauterine ischemia(IUI)
to understand pathogenesis. Researches used different methods to mimic IUI in
rat models. One of them is laparotomy which is used for induction of IUI by
clamping the uterine and ovarian vasculature for 20 minutes. In this example,
mechanical ventilation effect is done by injecting glycerol in the infants.
5 On the other hand, laparotomy is applied in the same way, but
mechanical ventilation is applied by using face mask. 2 In another
case, low-dose maternal lipopolysaccharide(mLPS) is also used addition to
prenatal IUI. 6 Depend on these kind of studies, researchers
defined damaged section of brain in infant rats where are chroid plexus, the
ependymal lining of lateral ventricles, internal capsule, periventricular
hemorrhages involving the subventricular zone, hippocampus, corpus callosum and
white matter in briefly generally shown in periventricular tissues. 5

SUR1 which stands for the sulfonylurea receptor 1 regulated by
NCCa-ATP channel normally is not expressed constitutively but in the
case of central nervous system(CNS) injuries, its transcription is upregulated.
7 As mentioned above, IUI is also several effects in CNS injuries.
Thus, it was determined that SUR1 is upregulated by result of IUI and its
expression is shown in tissues as mentioned above. 5 When
inhibitor of SUR1 is used which is glibenclamide, the upregulation of SUR1
expression is inhibited in the damaged section of the brain as indicated above.
3 Glibenclamide is administered to mother rat which is at the end of
pregnancy shows that infants are protected from prenatal IUI by reducing brain
hemorrhages. Also, it prevents later cognitive disabilities in rats. 5

The recent studies show that prenatal IUI with mechanical
ventilation (can also with mLPS treatment) induces the angiogenesis by
activation of MMP-9. MMP-9 which is matrix metalloproteinase-9 role in local
proteolysis of the extracellular matrix. Collagen IV and laminin are the
important substrate of it, so its activation is accompanied by loss of its
substrates. Collagen IV and laminin are the important components of the
microvessels in the periventricular tissues. They have role in integrity and
composition of microvessels. Thus, degradation of collagen IV and laminin cause
hemorrhages in periventricular area and it further causes inflammation. 2
On the other hand, hypoxia inducible factor 1(HIF-1) is also activated by
induce of prenatal IUI. HIF-1 have important role in transcriptional
upregulation of genes which regulates new vessel formation and proteolytic
matrix degradation. 8 Thus, it also causes the increment of MMP-9
and VEGF production to cause of edema and blood brain barrier permeability
increment. 2 Additionally, HIF-1 is important key regulator of
SUR1. Specificity protein 1 and HIF-1 induces the the Abcc8 gene to production
of SUR1. Ischemic stroke causes this regulation of SUR1. Thus, prenatal
ischemia can also cause this situation. 8

The outcome of these studies is that SUR1 and MMP-9
upregulation affect the same region of the brain which is periventricular
region and HIF-1 is responsible for both production in the same manner. 2,5,8
Thus, it is hypothesized that SUR1 and MMP-9 could be interacted or they can
affect activation and upregulation of each other by signaling. Thus, if their
activation is depending on each other, inhibition of one of them also affects
the other one’s activation negatively.