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Perspective of synaptic protection after post-infarction treatment with statins.

Gutiérrez-Vargas JA, Cespedes-Rubio A, Cardona-Gómez GP - J Transl Med (2015)

Bottom Line: Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments.The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models.Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood-brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.

View Article: PubMed Central - PubMed

Affiliation: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, School of Medicine, SIU, University of Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia. sciranou@gmail.com.

ABSTRACT
Stroke is the second most common cause of death in people over 45 years of age in Colombia and is the leading cause of permanent disability worldwide. Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments. The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models. However, in clinical trials, most of these drugs do not reproduce the previously demonstrated neuroprotective property, and some even have adverse effects that had not previously been detected in animal experimentation.Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Several studies have shown that statin therapy in an animal model of focal cerebral ischemia reduces infarct volume, as well as markers of neurodegeneration, activates neuronal survival pathways, and improves performance on learning and memory tests. Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood-brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.

No MeSH data available.


Related in: MedlinePlus

Neurodegeneration and protection in a focal cerebral ischemia model in rats. A) Histopathology of focal cerebral ischemia (tMCAO) model in rats. a) Panoramic representative image of a whole rat brain with tMCAO injury. b) Contralateral and ipsilateral images from cerebral ischemic rat tissue with Hematoxilin-eosin staining at the −3,80 mm bregma. LH = left hemisphere, RH = Right hemisphere, square = Selected area from CA1 area. Scale bar = 1,7 mm. c), d), e) Left side representative images from Sham rats and Right side representative images from ischemic rats. c) Hematoxilin-eosin staining 100x from CA1 square in b). Scale bar = 50 μm. d) Hyperphosphorylated tau immunoreactivity (AT-8) staining 40X in CA1 area. Scale bar = 70 μm. e) Fluorojade staining 10x. Scale bar = 100 μm. B), C) and D) Comparative hypothetical model of synaptic proteins alteration following cerebral ischemia and Atorvastatin treatment. B) Sham, C) Ischemia and D) ATV-treated ischemia. B) Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are associated in a normal condition (Sh = Sham). C) Glutamate receptors are uncoupled from PSD-95 and are accumulated in the cytoplasm due to retention of subunits in the endoplasmic reticulum (ER) because of the loss of transport toward synapses due to the alteration of microtubules and the cytoskeleton. Proteins that regulate the cytoskeleton, such as RhoA increased and synaptic complexes formed by the complex cadherins/catenins, glutamate receptors, and post-synaptic proteins, such as PSD-95 are lost. D) Model of protection by statins after cerebral ischemia. Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are restored in synapse, inducing neuronal connectivity. ISCH= Ischemia, ATV = Atorvastatin.
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Fig1: Neurodegeneration and protection in a focal cerebral ischemia model in rats. A) Histopathology of focal cerebral ischemia (tMCAO) model in rats. a) Panoramic representative image of a whole rat brain with tMCAO injury. b) Contralateral and ipsilateral images from cerebral ischemic rat tissue with Hematoxilin-eosin staining at the −3,80 mm bregma. LH = left hemisphere, RH = Right hemisphere, square = Selected area from CA1 area. Scale bar = 1,7 mm. c), d), e) Left side representative images from Sham rats and Right side representative images from ischemic rats. c) Hematoxilin-eosin staining 100x from CA1 square in b). Scale bar = 50 μm. d) Hyperphosphorylated tau immunoreactivity (AT-8) staining 40X in CA1 area. Scale bar = 70 μm. e) Fluorojade staining 10x. Scale bar = 100 μm. B), C) and D) Comparative hypothetical model of synaptic proteins alteration following cerebral ischemia and Atorvastatin treatment. B) Sham, C) Ischemia and D) ATV-treated ischemia. B) Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are associated in a normal condition (Sh = Sham). C) Glutamate receptors are uncoupled from PSD-95 and are accumulated in the cytoplasm due to retention of subunits in the endoplasmic reticulum (ER) because of the loss of transport toward synapses due to the alteration of microtubules and the cytoskeleton. Proteins that regulate the cytoskeleton, such as RhoA increased and synaptic complexes formed by the complex cadherins/catenins, glutamate receptors, and post-synaptic proteins, such as PSD-95 are lost. D) Model of protection by statins after cerebral ischemia. Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are restored in synapse, inducing neuronal connectivity. ISCH= Ischemia, ATV = Atorvastatin.

Mentions: In focal ischemia, the region that suffers the most severe degree of hypoperfusion progresses rapidly towards irreversible damage due to a necrotic death, which represents the ischemic core. This area exhibits low cerebral blood flow (<10% of the baseline value) and the irreversible failure of energy metabolism [10]. The remaining hypoperfused tissue surrounding the ischemic core has an imbalance in the mechanisms of the autoregulation of blood flow and is known as the penumbra zone [11,12]. In this region, neurons show alterations in functionality, although they retain a minimum metabolic activity that preserves structural integrity for a longer period of time, following a pattern of apoptotic death (Figure 1A) [13,14]. The penumbra is potentially recoverable and, as such, represents a key target for therapeutic intervention in cerebral ischemia [15]; however, unless perfusion is improved or the cells become relatively resistant to the injury, the cells of the penumbra zone are at risk of dying within a few hours by necrosis [10,16].Figure 1


Perspective of synaptic protection after post-infarction treatment with statins.

Gutiérrez-Vargas JA, Cespedes-Rubio A, Cardona-Gómez GP - J Transl Med (2015)

Neurodegeneration and protection in a focal cerebral ischemia model in rats. A) Histopathology of focal cerebral ischemia (tMCAO) model in rats. a) Panoramic representative image of a whole rat brain with tMCAO injury. b) Contralateral and ipsilateral images from cerebral ischemic rat tissue with Hematoxilin-eosin staining at the −3,80 mm bregma. LH = left hemisphere, RH = Right hemisphere, square = Selected area from CA1 area. Scale bar = 1,7 mm. c), d), e) Left side representative images from Sham rats and Right side representative images from ischemic rats. c) Hematoxilin-eosin staining 100x from CA1 square in b). Scale bar = 50 μm. d) Hyperphosphorylated tau immunoreactivity (AT-8) staining 40X in CA1 area. Scale bar = 70 μm. e) Fluorojade staining 10x. Scale bar = 100 μm. B), C) and D) Comparative hypothetical model of synaptic proteins alteration following cerebral ischemia and Atorvastatin treatment. B) Sham, C) Ischemia and D) ATV-treated ischemia. B) Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are associated in a normal condition (Sh = Sham). C) Glutamate receptors are uncoupled from PSD-95 and are accumulated in the cytoplasm due to retention of subunits in the endoplasmic reticulum (ER) because of the loss of transport toward synapses due to the alteration of microtubules and the cytoskeleton. Proteins that regulate the cytoskeleton, such as RhoA increased and synaptic complexes formed by the complex cadherins/catenins, glutamate receptors, and post-synaptic proteins, such as PSD-95 are lost. D) Model of protection by statins after cerebral ischemia. Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are restored in synapse, inducing neuronal connectivity. ISCH= Ischemia, ATV = Atorvastatin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4403706&req=5

Fig1: Neurodegeneration and protection in a focal cerebral ischemia model in rats. A) Histopathology of focal cerebral ischemia (tMCAO) model in rats. a) Panoramic representative image of a whole rat brain with tMCAO injury. b) Contralateral and ipsilateral images from cerebral ischemic rat tissue with Hematoxilin-eosin staining at the −3,80 mm bregma. LH = left hemisphere, RH = Right hemisphere, square = Selected area from CA1 area. Scale bar = 1,7 mm. c), d), e) Left side representative images from Sham rats and Right side representative images from ischemic rats. c) Hematoxilin-eosin staining 100x from CA1 square in b). Scale bar = 50 μm. d) Hyperphosphorylated tau immunoreactivity (AT-8) staining 40X in CA1 area. Scale bar = 70 μm. e) Fluorojade staining 10x. Scale bar = 100 μm. B), C) and D) Comparative hypothetical model of synaptic proteins alteration following cerebral ischemia and Atorvastatin treatment. B) Sham, C) Ischemia and D) ATV-treated ischemia. B) Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are associated in a normal condition (Sh = Sham). C) Glutamate receptors are uncoupled from PSD-95 and are accumulated in the cytoplasm due to retention of subunits in the endoplasmic reticulum (ER) because of the loss of transport toward synapses due to the alteration of microtubules and the cytoskeleton. Proteins that regulate the cytoskeleton, such as RhoA increased and synaptic complexes formed by the complex cadherins/catenins, glutamate receptors, and post-synaptic proteins, such as PSD-95 are lost. D) Model of protection by statins after cerebral ischemia. Synaptic complexes formed by proteins of synaptic adhesion (cadherins and catenins), glutamate receptors, and scaffold proteins, such as PSD-95 are restored in synapse, inducing neuronal connectivity. ISCH= Ischemia, ATV = Atorvastatin.
Mentions: In focal ischemia, the region that suffers the most severe degree of hypoperfusion progresses rapidly towards irreversible damage due to a necrotic death, which represents the ischemic core. This area exhibits low cerebral blood flow (<10% of the baseline value) and the irreversible failure of energy metabolism [10]. The remaining hypoperfused tissue surrounding the ischemic core has an imbalance in the mechanisms of the autoregulation of blood flow and is known as the penumbra zone [11,12]. In this region, neurons show alterations in functionality, although they retain a minimum metabolic activity that preserves structural integrity for a longer period of time, following a pattern of apoptotic death (Figure 1A) [13,14]. The penumbra is potentially recoverable and, as such, represents a key target for therapeutic intervention in cerebral ischemia [15]; however, unless perfusion is improved or the cells become relatively resistant to the injury, the cells of the penumbra zone are at risk of dying within a few hours by necrosis [10,16].Figure 1

Bottom Line: Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments.The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models.Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood-brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.

View Article: PubMed Central - PubMed

Affiliation: Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, School of Medicine, SIU, University of Antioquia UdeA, Calle 70 No. 52-21, Medellín, Colombia. sciranou@gmail.com.

ABSTRACT
Stroke is the second most common cause of death in people over 45 years of age in Colombia and is the leading cause of permanent disability worldwide. Cerebral ischemia is a stroke characterized by decreased blood flow due to the occlusion of one or more cerebral arteries, which can cause memory problems and hemiplegia or paralysis, among other impairments. The literature contains hundreds of therapies (invasive and noninvasive) that exhibit a neuroprotective effect when evaluated in animal models. However, in clinical trials, most of these drugs do not reproduce the previously demonstrated neuroprotective property, and some even have adverse effects that had not previously been detected in animal experimentation.Statins are drugs that inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. Several studies have shown that statin therapy in an animal model of focal cerebral ischemia reduces infarct volume, as well as markers of neurodegeneration, activates neuronal survival pathways, and improves performance on learning and memory tests. Given the implied therapeutic benefit and the limited understanding of the mechanism of action of statins in brain repair, it is necessary to address the biochemical and tissue effects of these drugs on synaptic proteins, such as NMDA receptors, synaptic adhesion proteins, and cytoskeletal proteins; these proteins are highly relevant therapeutic targets, which, in addition to giving a structural account of synaptic connectivity and function, are also indicators of cellular communication and the integrity of the blood-brain barrier, which are widely affected in the long term post-cerebral infarct but, interestingly, are protected by statins when administered during the acute phase.

No MeSH data available.


Related in: MedlinePlus