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studies showed that NEIL3 was cell cycle‑regulated In conclusion, there is evidence that NEIL1 might
with the highest expression in the G2 phase. [32,33] play an important role in ischemia stroke, but the
Thus far, NEIL3 proteins have not been found in the exact functions of NEIL1 during the pathophysiologic
mitochondria. [23] development of cerebral ischemia are still unknown.

In conclusion, distribution of NEIL3 is very different NEIL2
from other DNA glycosylases which suggests a As previously mentioned, Rolseth et al. [35] found that
special function of NEIL3 in a mammal. In the similarly to NEIL1, the expression of NEIL2 is not
central nervous system, NEIL3 expression in both changed in response to OGD treatment in CA1. To date,
human and mouse brain has been localized to regions we still know very little about the relationship between
where neurogenesis takes place. NEIL3 seems to be NEIL2 and ischemic stroke. Future studies are needed
upregulated in tumor tissues compared to normal to completely understand if and how NEIL2 could be
tissues. In summary, the expression patterns of associated with ischemic stroke.
NEIL3 suggest that mammalian NEIL3 seems to be
highly expressed in cells that have high proliferative NEIL3
potential. Similarly to NEIL1, the transcription of NEIL3 is
significantly reduced in the hippocampus and
THE NEIL AND ISCHEMIC STROKE cerebellum by hypothermia as observed in a study
on newborn pigs exposed to hypoxia, however, no
NEIL1 significant effect on the accumulation of oxidative
The interest in the relationship between NEILs DNA damage in genomic DNA was found. [36] In order
and stroke arises from the work done by Rolseth to understand the relationship between NEIL3 and
et al. [35] By observing BER activities in organotypic hypoxia‑ischemia, Sejersted et al. [29] carried out an
hippocampal slice culture exposed to oxygen and experiment on NEIL3 gene knockout (NEIL3‑null)
glucose deprivation, the authors found that CA1 has mice in vitro and in vivo. Interestingly, after
a lower capacity than CA3/FD in base lesions removal hypoxia‑ischemia, there is no increase of cellular
under basal conditions, which may be correlated damage or death in vivo in NEIL3‑null mice at an
with the low expression levels of both NEIL1 and early stage, but a significant deficient in reconstituted
NEIL2. [35] This study has not only demonstrated the neuronal tissue after 42 d. NEIL3‑null neurospheres
reasons why CA1 was vulnerable to ischemic stroke exhibited poor growth and skewed differentiation
but also revealed the potential unique role that DNA that could explain the poor outcome of NEIL3‑null
glycosylases might play in ischemic stroke. [35] By mice after hypoxic ischemia. In agreement with the
addressing the effect of hyperoxic reoxygenation aforementioned expression pattern, this study has
and therapeutic hypothermia on the development demonstrated that NEIL3 seems to predominantly play
of brain damage after asphyxia in newborn pigs, a role in neurogenesis. NEIL3‑null mice also showed
Dalen et al. [36] found out that NEIL1 is significantly learning and memory deficits and reduced anxiety‑like
downregulated in the hippocampus, cortex, behavior, and synaptic irregularities in hippocampal
striatum, and liver upon hypothermia without any neurons. [31] Future studies addressing the role of NEIL3
detective effect on the accumulation of oxidative in neuronal tissue in ischemic stroke will shed more
DNA damage in genomic DNA. In addition, like light on this issue.
OGG1, NEIL1 expression in the brain is unaffected
by hyperoxia. A recent study by Canugovi et al. [37] CONCLUSIONS AND FUTURE PERSPECTIVES
demonstrated that NEIL1 can be linked to changes
in ischemic stroke. Due to the increasing brain As a consequence of high oxygen metabolism, an
damage caused by reducing the incision capacity efficient BER pathway is activated to ensure genomic
on a 5‑hydroxyuracil‑containing bubble substrate, stability and brain homeostasis. NEILs have been
NEIL1 gene knockout mice exhibited impaired discovered in 2002 and since then studies have reported
memory retention in a water maze test, but no that these proteins are mainly expressed in the brain.
abnormalities in motor performance, anxiety, or However, all these data have not clearly elucidated the
fear conditioning. These results indicate that NEIL1 expression pattern and the relationship between the
plays an important role in learning and memory and changes in NEILs and ischemic stroke. Although, there
in the protection of neurons against ischemic injury. is evidence that DNA glycosylases deficiency impacts
Interestingly, NEIL1 gene knockout mice display a on brain function in animal models, the molecular
specific metabolic phenotype, which is attributed to mechanism is still unknown. In the future, there is hope
the increased mitochondrial DNA damage. [38] that by characterizing the effect of NEILs on subclasses

284 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 Neuroimmunol Neuroinflammation | Volume 2 | Issue 4 | October 15, 2015 285