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Stroke neuroprotection: targeting mitochondria.

Watts LT, Lloyd R, Garling RJ, Duong T - Brain Sci (2013)

Bottom Line: Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies.The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA).The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA. wattsl@uthscsa.edu.

ABSTRACT
Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies. The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA). However, this treatment is limited to within 4.5 h of stroke onset in a small subset of patients. The goal of this review is to focus on mitochondrial-dependent therapeutic agents that could provide neuroprotection following stroke. Dysfunctional mitochondria are linked to neurodegeneration in many disease processes including stroke. The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke.

No MeSH data available.


Related in: MedlinePlus

Purinergic receptor stimulation using 2-methylthioadenosine diphosphate trisodium salt (2meSADP) following middle cerebral artery occlusion (MCAO) rescues cortical cellular layers. Rats were treated with 100 μM 2meSADP 30 min post MCAO. Forty-eight hours following treatment the rats were sacrificed and triphenyltetrazolium chloride (TTC) staining was performed. (A) Histogram demonstrating the reduction in lesion volume with 2meSADP treatment. (B) Representative images from two different rats following MCAO with or without 2meSADP treatment. ** indicates p < 0.001 using student’s t-test.
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brainsci-03-00540-f004: Purinergic receptor stimulation using 2-methylthioadenosine diphosphate trisodium salt (2meSADP) following middle cerebral artery occlusion (MCAO) rescues cortical cellular layers. Rats were treated with 100 μM 2meSADP 30 min post MCAO. Forty-eight hours following treatment the rats were sacrificed and triphenyltetrazolium chloride (TTC) staining was performed. (A) Histogram demonstrating the reduction in lesion volume with 2meSADP treatment. (B) Representative images from two different rats following MCAO with or without 2meSADP treatment. ** indicates p < 0.001 using student’s t-test.

Mentions: 2-Methylthioadenosine diphosphate trisodium salt (2meSADP) is a selective, potent purinergic agonist for the P2Y1, P2Y12 and P2Y13 receptors with EC50 values of 8.29 and 9.05, 19 nM, respectively [74]. The chemical structure is found in Figure 3. 2meSADP enhances mitochondrial metabolism and has been shown to have protective effects in hypotension, bleeding disorders, thromboembolism and cardiovascular disease [75,76,77,78]. Neuroprotection following a stroke can be enhanced by increasing astrocyte mitochondrial metabolism via P2Y1 receptor activation using the agonist 2meSADP or MRS 2365 [79,80]. Two studies utilized the Rose Bengal photothrombosis stroke model to determine the effect of 2meSADP [80,81]. In this model, the photosensitive dye, Rose Bengal, is administered by tail vein and excited through a thinned cranium with a 562 nm light using a confocal microscope. This model causes a permanent clot in the vessels exposed to the laser. Rose Bengal generates ROS, which activates tissue factor (TF), the initiator of the coagulation cascade, and consequently triggers an extrinsic coagulation cascade, therefore producing an ischemic lesion that is pathologically very relevant to clinical stroke [82]. 2meSADP was found to markedly reduced infarct size in this model in mice and was hypothesized to occur by increasing calcium sensitive mitochondrial metabolism in astrocytes through G-protein coupled purinergic receptor stimulation [83]. In addition, it was observed that cytotoxic edema formation was also reversed following 2meSADP administration suggesting the importance of maintaining mitochondrial metabolism in multiple facets of the pathological consequences of a stroke. More recently, these findings were extended to demonstrate that stimulation of P2Y1R with 2meSAP also enhances neuronal survival following a stroke using transgenic mice expressing yellow fluorescent protein in neurons. Following stoke the morphological changes associated with neuronal death such as beading and swelling of dendrites were assessed and found to be reversed with 2meSADP treatment [81]. Mitochondrial membrane potentials were also found to be diminished following an infarct and were repolarized upon 2meSADP administration [81]. Utilizing a cerebral ischemia/reperfusion model of stroke (MCAO with 60 min reperfusion) we assessed the ability of 2meSADP to reduce lesion volume. Rats treated with 2meSADP (200 µg dose) at the time of reperfusion had significantly reduced lesion volumes demonstrated by 2,3,5-triphenyltetrazolium chloride (TTC) staining (common method for visualizing stroke volume) forty-eight hours after stroke (Figure 4). In summary, 2meSADP treatment (1) reduces neuronal cell death; (2) reverses ischemia-induced brain damage and swelling; (3) correlates with increased mitochondrial metabolism and neuroprotection and (4) depends on the expression of the IP3 receptor on astrocytes.


Stroke neuroprotection: targeting mitochondria.

Watts LT, Lloyd R, Garling RJ, Duong T - Brain Sci (2013)

Purinergic receptor stimulation using 2-methylthioadenosine diphosphate trisodium salt (2meSADP) following middle cerebral artery occlusion (MCAO) rescues cortical cellular layers. Rats were treated with 100 μM 2meSADP 30 min post MCAO. Forty-eight hours following treatment the rats were sacrificed and triphenyltetrazolium chloride (TTC) staining was performed. (A) Histogram demonstrating the reduction in lesion volume with 2meSADP treatment. (B) Representative images from two different rats following MCAO with or without 2meSADP treatment. ** indicates p < 0.001 using student’s t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061853&req=5

brainsci-03-00540-f004: Purinergic receptor stimulation using 2-methylthioadenosine diphosphate trisodium salt (2meSADP) following middle cerebral artery occlusion (MCAO) rescues cortical cellular layers. Rats were treated with 100 μM 2meSADP 30 min post MCAO. Forty-eight hours following treatment the rats were sacrificed and triphenyltetrazolium chloride (TTC) staining was performed. (A) Histogram demonstrating the reduction in lesion volume with 2meSADP treatment. (B) Representative images from two different rats following MCAO with or without 2meSADP treatment. ** indicates p < 0.001 using student’s t-test.
Mentions: 2-Methylthioadenosine diphosphate trisodium salt (2meSADP) is a selective, potent purinergic agonist for the P2Y1, P2Y12 and P2Y13 receptors with EC50 values of 8.29 and 9.05, 19 nM, respectively [74]. The chemical structure is found in Figure 3. 2meSADP enhances mitochondrial metabolism and has been shown to have protective effects in hypotension, bleeding disorders, thromboembolism and cardiovascular disease [75,76,77,78]. Neuroprotection following a stroke can be enhanced by increasing astrocyte mitochondrial metabolism via P2Y1 receptor activation using the agonist 2meSADP or MRS 2365 [79,80]. Two studies utilized the Rose Bengal photothrombosis stroke model to determine the effect of 2meSADP [80,81]. In this model, the photosensitive dye, Rose Bengal, is administered by tail vein and excited through a thinned cranium with a 562 nm light using a confocal microscope. This model causes a permanent clot in the vessels exposed to the laser. Rose Bengal generates ROS, which activates tissue factor (TF), the initiator of the coagulation cascade, and consequently triggers an extrinsic coagulation cascade, therefore producing an ischemic lesion that is pathologically very relevant to clinical stroke [82]. 2meSADP was found to markedly reduced infarct size in this model in mice and was hypothesized to occur by increasing calcium sensitive mitochondrial metabolism in astrocytes through G-protein coupled purinergic receptor stimulation [83]. In addition, it was observed that cytotoxic edema formation was also reversed following 2meSADP administration suggesting the importance of maintaining mitochondrial metabolism in multiple facets of the pathological consequences of a stroke. More recently, these findings were extended to demonstrate that stimulation of P2Y1R with 2meSAP also enhances neuronal survival following a stroke using transgenic mice expressing yellow fluorescent protein in neurons. Following stoke the morphological changes associated with neuronal death such as beading and swelling of dendrites were assessed and found to be reversed with 2meSADP treatment [81]. Mitochondrial membrane potentials were also found to be diminished following an infarct and were repolarized upon 2meSADP administration [81]. Utilizing a cerebral ischemia/reperfusion model of stroke (MCAO with 60 min reperfusion) we assessed the ability of 2meSADP to reduce lesion volume. Rats treated with 2meSADP (200 µg dose) at the time of reperfusion had significantly reduced lesion volumes demonstrated by 2,3,5-triphenyltetrazolium chloride (TTC) staining (common method for visualizing stroke volume) forty-eight hours after stroke (Figure 4). In summary, 2meSADP treatment (1) reduces neuronal cell death; (2) reverses ischemia-induced brain damage and swelling; (3) correlates with increased mitochondrial metabolism and neuroprotection and (4) depends on the expression of the IP3 receptor on astrocytes.

Bottom Line: Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies.The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA).The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA. wattsl@uthscsa.edu.

ABSTRACT
Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Blood flow deficit results in an expanding infarct core with a time-sensitive peri-infarct penumbra that is considered salvageable and is the primary target for treatment strategies. The only current FDA-approved drug for treating ischemic stroke is recombinant tissue plasminogen activator (rt-PA). However, this treatment is limited to within 4.5 h of stroke onset in a small subset of patients. The goal of this review is to focus on mitochondrial-dependent therapeutic agents that could provide neuroprotection following stroke. Dysfunctional mitochondria are linked to neurodegeneration in many disease processes including stroke. The mechanisms reviewed include: (1) increasing ATP production by purinergic receptor stimulation, (2) decreasing the production of ROS by superoxide dismutase, or (3) increasing antioxidant defenses by methylene blue, and their benefits in providing neuroprotection following a stroke.

No MeSH data available.


Related in: MedlinePlus