What the hell is it going to take to translate something as simple as aspirin into a stroke protocol? Or is the stroke world so fucked up that it can't get something this blasted simple into clinical use for 30 years? Ask your damned neurologist why they aren't using this in 1 month.
Jing Chen1†, imageShilun Zuo1,2†, imageJing Wang1, imageJian Huang1, imageXiao Zhang1, imageYang Liu1, imageYunxia Zhang1, imageJun Zhao1, imageJunliang Han1, imageLize Xiong3, imageMing Shi1* and imageZhirong Liu1*
1Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
2Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
3Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Cerebral white matter lesion (WML) is one of the main causes for cognitive impairment and is often caused by chronic cerebral hypoperfusion. A line of evidence has shown that aspirin has neuroprotective effects and produces some benefits in long-term outcome and survival for ischemic stroke patients. However, whether aspirin exerts a protective effect against WML is still largely unknown. Here, we showed that aspirin could promote oligodendrocyte precursor cell (OPC) proliferation and differentiation into oligodendrocytes after WML. Male Sprague-Dawley rats were subjected to permanent bilateral common carotid artery occlusion, a well-established model for WML. Four weeks later, Morris water maze test showed an impairment of learning and memory ability of rat while aspirin treatment improved behavioral performance. Low dose of aspirin (25 mg/kg) was found to elevate the number of OPCs while relatively high doses (100–200 mg/kg) increased that of oligodendrocytes, and ameliorated WML-induced the thinning of myelin, as revealed by the electron microscope. Similarly, our in vitro study also showed that relatively low and high doses of aspirin enhanced OPC proliferation and differentiation into oligodendrocytes, respectively. Furthermore, we revealed that aspirin enhanced extracellular signal-related kinase (ERK) but inhibited RhoA activities. In summary, we provided the first evidence that aspirin can promote oligodendrogenesis and oligodendrocyte myelination after WML, which may involve ERK and RhoA pathways.
Introduction
Cerebral white matter lesions (WML) are observed in aging and stroke and constitute the core pathology of Binswanger disease, a form of subcortical vascular dementia (Shibata et al., 2004). These WML are believed to be responsible for cognitive impairment and are caused by chronic cerebral hypoperfusion (Pantoni and Garcia, 1997). There is an evidence suggesting that the cerebral white matter is as vulnerable to ischemia as cerebral gray matter (Pantoni et al., 1996). Dewar et al. (1999) emphasized that total brain protection, in which not only gray matter but also white matter is protected, is important and necessary.
However, damage to white matter, which is composed of myelinated axons and oligodendrocytes, has been largely neglected. Multiple mechanisms were involved in WML. For example, maturation-dependent vulnerability in the oligodendrocyte lineage was found in a hypoxic–ischemic injury model (Back et al., 2002). Oligodendrocytes are best known as the myelin-forming cells in the central nervous system (CNS). Oligodendrocyte precursor cells (OPCs) are immature oligodendrocytes and can differentiate into myelin-forming cells under certain conditions (Fu et al., 2005). In the adult brain, mature myelinating oligodendrocytes are continuously produced from local OPCs residing in the brain parenchyma (Gensert and Goldman, 1997; Fancy et al., 2004) and from precursor cells located in the subventricular zone (Picard-Riera et al., 2002; Fancy et al., 2004; Menn et al., 2006). Given their high migratory potential and their ability to differentiate into myelin-forming cells, subventricular neural stem cells (NSCs) represent an important endogenous source of OPCs for preserving the oligodendrocyte population in the white matter and for the repair of demyelinating injuries (Gonzalez-Perez and Alvarez-Buylla, 2011). Therefore, it is proposed that any drug, which can increase the number of OPCs and/or oligodendrocytes, may be beneficial for the treatment of WML.
Aspirin has become a standard treatment for acute ischemic stroke since it produces some benefit in long-term outcome and survival if given within 14 days of stroke onset (Hankey et al., 2003). Depending on its dosage, aspirin has a wide spectrum of pharmacological activities and multiple sites of action, which may contribute to the neuroprotection (Berger et al., 2004). So far, numerous studies have shown the neuroprotective effects of aspirin (Lorenzo Fernandez, 2002; Castillo et al., 2003; Vartiainen et al., 2003; Berger et al., 2004; Asanuma et al., 2012). For example, aspirin was found to be protective against ischemia-induced neuronal damage in animal model (Castillo et al., 2003; Berger et al., 2004) and in patients (Castillo et al., 2003), and against dopamine quinone-induced neurotoxicity (Asanuma et al., 2012). Based on the evidence above, we proposed that aspirin might exert a protective action against WML. Thus, in this study, using a well-established WML model induced by chronic cerebral hypoperfusion, we examined the effects of different doses of aspirin on rat learning and memory ability and the changes in the expression of oligodendrocyte lineage markers, and further explored underlying mechanisms of aspirin.
- See more at: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00007/full?#sthash.NXiuyWyM.dpuf
Cerebral white matter lesion (WML) is one of the main causes for
cognitive impairment and is often caused by chronic cerebral
hypoperfusion. A line of evidence has shown that aspirin has
neuroprotective effects and produces some benefits in long-term outcome
and survival for ischemic stroke patients. However, whether aspirin
exerts a protective effect against WML is still largely unknown. Here,
we showed that aspirin could promote oligodendrocyte precursor cell
(OPC) proliferation and differentiation into oligodendrocytes after WML.
Male Sprague-Dawley rats were subjected to permanent bilateral common
carotid artery occlusion, a well-established model for WML. Four weeks
later, Morris water maze test showed an impairment of learning and
memory ability of rat while aspirin treatment improved behavioral
performance. Low dose of aspirin (25 mg/kg) was found to elevate the
number of OPCs while relatively high doses (100–200 mg/kg) increased
that of oligodendrocytes, and ameliorated WML-induced the thinning of
myelin, as revealed by the electron microscope. Similarly, our in vitro
study also showed that relatively low and high doses of aspirin
enhanced OPC proliferation and differentiation into oligodendrocytes,
respectively. Furthermore, we revealed that aspirin enhanced
extracellular signal-related kinase (ERK) but inhibited RhoA activities.
In summary, we provided the first evidence that aspirin can promote
oligodendrogenesis and oligodendrocyte myelination after WML, which may
involve ERK and RhoA pathways.
Introduction
Cerebral white matter lesions (WML) are observed in
aging and stroke and constitute the core pathology of Binswanger
disease, a form of subcortical vascular dementia (
Shibata et al., 2004). These WML are believed to be responsible for cognitive impairment and are caused by chronic cerebral hypoperfusion (
Pantoni and Garcia, 1997). There is an evidence suggesting that the cerebral white matter is as vulnerable to ischemia as cerebral gray matter (
Pantoni et al., 1996).
Dewar et al. (1999)
emphasized that total brain protection, in which not only gray matter
but also white matter is protected, is important and necessary.
However, damage to white matter, which is composed of
myelinated axons and oligodendrocytes, has been largely neglected.
Multiple mechanisms were involved in WML. For example,
maturation-dependent vulnerability in the oligodendrocyte lineage was
found in a hypoxic–ischemic injury model (
Back et al., 2002).
Oligodendrocytes are best known as the myelin-forming cells in the
central nervous system (CNS). Oligodendrocyte precursor cells (OPCs) are
immature oligodendrocytes and can differentiate into myelin-forming
cells under certain conditions (
Fu et al., 2005).
In the adult brain, mature myelinating oligodendrocytes are
continuously produced from local OPCs residing in the brain parenchyma (
Gensert and Goldman, 1997;
Fancy et al., 2004) and from precursor cells located in the subventricular zone (
Picard-Riera et al., 2002;
Fancy et al., 2004;
Menn et al., 2006).
Given their high migratory potential and their ability to differentiate
into myelin-forming cells, subventricular neural stem cells (NSCs)
represent an important endogenous source of OPCs for preserving the
oligodendrocyte population in the white matter and for the repair of
demyelinating injuries (
Gonzalez-Perez and Alvarez-Buylla, 2011).
Therefore, it is proposed that any drug, which can increase the number
of OPCs and/or oligodendrocytes, may be beneficial for the treatment of
WML.
Aspirin has become a standard treatment for acute
ischemic stroke since it produces some benefit in long-term outcome and
survival if given within 14 days of stroke onset (
Hankey et al., 2003).
Depending on its dosage, aspirin has a wide spectrum of pharmacological
activities and multiple sites of action, which may contribute to the
neuroprotection (
Berger et al., 2004). So far, numerous studies have shown the neuroprotective effects of aspirin (
Lorenzo Fernandez, 2002;
Castillo et al., 2003;
Vartiainen et al., 2003;
Berger et al., 2004;
Asanuma et al., 2012). For example, aspirin was found to be protective against ischemia-induced neuronal damage in animal model (
Castillo et al., 2003;
Berger et al., 2004) and in patients (
Castillo et al., 2003), and against dopamine quinone-induced neurotoxicity (
Asanuma et al., 2012).
Based on the evidence above, we proposed that aspirin might exert a
protective action against WML. Thus, in this study, using a
well-established WML model induced by chronic cerebral hypoperfusion, we
examined the effects of different doses of aspirin on rat learning and
memory ability and the changes in the expression of oligodendrocyte
lineage markers, and further explored underlying mechanisms of aspirin.
- See more at: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00007/full?#sthash.NXiuyWyM.dpuf
Jing Chen
1†,
Shilun Zuo
1,2†,
Jing Wang
1,
Jian Huang
1,
Xiao Zhang
1,
Yang Liu
1,
Yunxia Zhang
1,
Jun Zhao
1,
Junliang Han
1,
Lize Xiong
3,
Ming Shi
1* and
Zhirong Liu1*
- 1Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- 2Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China
- 3Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
Cerebral white matter lesion (WML) is one of the main causes for
cognitive impairment and is often caused by chronic cerebral
hypoperfusion. A line of evidence has shown that aspirin has
neuroprotective effects and produces some benefits in long-term outcome
and survival for ischemic stroke patients. However, whether aspirin
exerts a protective effect against WML is still largely unknown. Here,
we showed that aspirin could promote oligodendrocyte precursor cell
(OPC) proliferation and differentiation into oligodendrocytes after WML.
Male Sprague-Dawley rats were subjected to permanent bilateral common
carotid artery occlusion, a well-established model for WML. Four weeks
later, Morris water maze test showed an impairment of learning and
memory ability of rat while aspirin treatment improved behavioral
performance. Low dose of aspirin (25 mg/kg) was found to elevate the
number of OPCs while relatively high doses (100–200 mg/kg) increased
that of oligodendrocytes, and ameliorated WML-induced the thinning of
myelin, as revealed by the electron microscope. Similarly, our
in vitro
study also showed that relatively low and high doses of aspirin
enhanced OPC proliferation and differentiation into oligodendrocytes,
respectively. Furthermore, we revealed that aspirin enhanced
extracellular signal-related kinase (ERK) but inhibited RhoA activities.
In summary, we provided the first evidence that aspirin can promote
oligodendrogenesis and oligodendrocyte myelination after WML, which may
involve ERK and RhoA pathways.
Introduction
Cerebral white matter lesions (WML) are observed in
aging and stroke and constitute the core pathology of Binswanger
disease, a form of subcortical vascular dementia (
Shibata et al., 2004). These WML are believed to be responsible for cognitive impairment and are caused by chronic cerebral hypoperfusion (
Pantoni and Garcia, 1997). There is an evidence suggesting that the cerebral white matter is as vulnerable to ischemia as cerebral gray matter (
Pantoni et al., 1996).
Dewar et al. (1999)
emphasized that total brain protection, in which not only gray matter
but also white matter is protected, is important and necessary.
However, damage to white matter, which is composed of
myelinated axons and oligodendrocytes, has been largely neglected.
Multiple mechanisms were involved in WML. For example,
maturation-dependent vulnerability in the oligodendrocyte lineage was
found in a hypoxic–ischemic injury model (
Back et al., 2002).
Oligodendrocytes are best known as the myelin-forming cells in the
central nervous system (CNS). Oligodendrocyte precursor cells (OPCs) are
immature oligodendrocytes and can differentiate into myelin-forming
cells under certain conditions (
Fu et al., 2005).
In the adult brain, mature myelinating oligodendrocytes are
continuously produced from local OPCs residing in the brain parenchyma (
Gensert and Goldman, 1997;
Fancy et al., 2004) and from precursor cells located in the subventricular zone (
Picard-Riera et al., 2002;
Fancy et al., 2004;
Menn et al., 2006).
Given their high migratory potential and their ability to differentiate
into myelin-forming cells, subventricular neural stem cells (NSCs)
represent an important endogenous source of OPCs for preserving the
oligodendrocyte population in the white matter and for the repair of
demyelinating injuries (
Gonzalez-Perez and Alvarez-Buylla, 2011).
Therefore, it is proposed that any drug, which can increase the number
of OPCs and/or oligodendrocytes, may be beneficial for the treatment of
WML.
Aspirin has become a standard treatment for acute
ischemic stroke since it produces some benefit in long-term outcome and
survival if given within 14 days of stroke onset (
Hankey et al., 2003).
Depending on its dosage, aspirin has a wide spectrum of pharmacological
activities and multiple sites of action, which may contribute to the
neuroprotection (
Berger et al., 2004). So far, numerous studies have shown the neuroprotective effects of aspirin (
Lorenzo Fernandez, 2002;
Castillo et al., 2003;
Vartiainen et al., 2003;
Berger et al., 2004;
Asanuma et al., 2012). For example, aspirin was found to be protective against ischemia-induced neuronal damage in animal model (
Castillo et al., 2003;
Berger et al., 2004) and in patients (
Castillo et al., 2003), and against dopamine quinone-induced neurotoxicity (
Asanuma et al., 2012).
Based on the evidence above, we proposed that aspirin might exert a
protective action against WML. Thus, in this study, using a
well-established WML model induced by chronic cerebral hypoperfusion, we
examined the effects of different doses of aspirin on rat learning and
memory ability and the changes in the expression of oligodendrocyte
lineage markers, and further explored underlying mechanisms of aspirin.
- See more at: http://journal.frontiersin.org/Journal/10.3389/fnagi.2014.00007/full?#sthash.NXiuyWyM.dpuf
