Limits...
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

Neuroprotection can be enhanced by stimulating Calcium-dependent astrocyte mitochondrial metabolism. The binding of 2-methylthioadenosine diphosphate trisodium salt(2meSADP) to the purinergic receptor (P2Y1R) activates the Inositol triphosphate (IP3) cascade resulting in release of calcium (Ca2+) from endoplasmic stores. The result is increased adenosine triphosphate (ATP) production within the mitochondria which provides for increased cellular demands following injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061853&req=5

brainsci-03-00540-f002: Neuroprotection can be enhanced by stimulating Calcium-dependent astrocyte mitochondrial metabolism. The binding of 2-methylthioadenosine diphosphate trisodium salt(2meSADP) to the purinergic receptor (P2Y1R) activates the Inositol triphosphate (IP3) cascade resulting in release of calcium (Ca2+) from endoplasmic stores. The result is increased adenosine triphosphate (ATP) production within the mitochondria which provides for increased cellular demands following injury.

Mentions: P2Y-receptors consist of eight mammalian subtypes (P2Y1,2,3,6,11,12,13,14). A majority of the P2Y-receptors signal through coupling to Gq/11, with only the P2Y12, P2Y13 and P2Y14 signaling through Gi/o. Activation of P2Y-receptors initiates a number of signaling cascades including phospholipases (PLCĪ², PLD, PLA2), adenylyl cyclase (AC) and mitogen-activated protein kinases (MAPK/MEK kinase). Purinergic receptor (P2Y1R) activation provides a mechanism whereby local extracellular signals can rapidly elevate intracellular calcium levels through increased production of inositol triphosphate (IP3) [68,69]. IP3-mediated calcium release increases mitochondrial calcium and consequently, increases respiration and ATP production [70,71,72,73] (Figure 2).


Stroke neuroprotection: targeting mitochondria.

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

Neuroprotection can be enhanced by stimulating Calcium-dependent astrocyte mitochondrial metabolism. The binding of 2-methylthioadenosine diphosphate trisodium salt(2meSADP) to the purinergic receptor (P2Y1R) activates the Inositol triphosphate (IP3) cascade resulting in release of calcium (Ca2+) from endoplasmic stores. The result is increased adenosine triphosphate (ATP) production within the mitochondria which provides for increased cellular demands following injury.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

brainsci-03-00540-f002: Neuroprotection can be enhanced by stimulating Calcium-dependent astrocyte mitochondrial metabolism. The binding of 2-methylthioadenosine diphosphate trisodium salt(2meSADP) to the purinergic receptor (P2Y1R) activates the Inositol triphosphate (IP3) cascade resulting in release of calcium (Ca2+) from endoplasmic stores. The result is increased adenosine triphosphate (ATP) production within the mitochondria which provides for increased cellular demands following injury.
Mentions: P2Y-receptors consist of eight mammalian subtypes (P2Y1,2,3,6,11,12,13,14). A majority of the P2Y-receptors signal through coupling to Gq/11, with only the P2Y12, P2Y13 and P2Y14 signaling through Gi/o. Activation of P2Y-receptors initiates a number of signaling cascades including phospholipases (PLCĪ², PLD, PLA2), adenylyl cyclase (AC) and mitogen-activated protein kinases (MAPK/MEK kinase). Purinergic receptor (P2Y1R) activation provides a mechanism whereby local extracellular signals can rapidly elevate intracellular calcium levels through increased production of inositol triphosphate (IP3) [68,69]. IP3-mediated calcium release increases mitochondrial calcium and consequently, increases respiration and ATP production [70,71,72,73] (Figure 2).

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