Limits...
A program for solving the brain ischemia problem.

DeGracia DJ - Brain Sci (2013)

Bottom Line: We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection.Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery.We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Wayne State University, 4116 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA. ddegraci@med.wayne.edu.

ABSTRACT
Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of "master bifurcation diagrams" that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection.

No MeSH data available.


Related in: MedlinePlus

(A) Polysome profile for nonischemic, sham-operated controls (NIC) CA1. Westerns of fractions for ribosomal proteins S6 and L7a, marking 40S and 60S subunits, respectively. eIF4E is translation initiation factor 4E. Boxes mark polysome-bound (B) and unbound (U) fractions. (B) Gene distances for CA1 and CA3 polysome bound (dB) and polysome-unbound (dU) fractions. (C) gene expression dynamics inspector (GEDI) analysis of microarray 8hR/NIC (R/N) class comparisons. S ~ dB/(dB+dU).
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brainsci-03-00460-f010: (A) Polysome profile for nonischemic, sham-operated controls (NIC) CA1. Westerns of fractions for ribosomal proteins S6 and L7a, marking 40S and 60S subunits, respectively. eIF4E is translation initiation factor 4E. Boxes mark polysome-bound (B) and unbound (U) fractions. (B) Gene distances for CA1 and CA3 polysome bound (dB) and polysome-unbound (dU) fractions. (C) gene expression dynamics inspector (GEDI) analysis of microarray 8hR/NIC (R/N) class comparisons. S ~ dB/(dB+dU).

Mentions: Our experimental groups were microdissected hippocampal CA1 and CA3 at 8hR in rat, and in NICs. There were n = 15 animals in each group. Homogenates from 5 animals per group were randomly pooled to give 3 replicates per group. Pooling was necessary to provide enough material to prepare polysome profiles by gradient centrifugation. RNA was extracted from: (1) polysome-containing fractions (polysome-bound mRNAs, B), and (2) the light gradient fractions that did not contain polysomes (polysome unbound, U) (Figure 10A). Next, 24 microarrays were performed for 8 experimental groups (n = 3 microarrays/group): NIC CA1B, NIC CA1U, NIC CA3B, NIC CA3U, 8hR CA1B, 8hR CA1U, 8hR CA3B, and 8hR CA3U.


A program for solving the brain ischemia problem.

DeGracia DJ - Brain Sci (2013)

(A) Polysome profile for nonischemic, sham-operated controls (NIC) CA1. Westerns of fractions for ribosomal proteins S6 and L7a, marking 40S and 60S subunits, respectively. eIF4E is translation initiation factor 4E. Boxes mark polysome-bound (B) and unbound (U) fractions. (B) Gene distances for CA1 and CA3 polysome bound (dB) and polysome-unbound (dU) fractions. (C) gene expression dynamics inspector (GEDI) analysis of microarray 8hR/NIC (R/N) class comparisons. S ~ dB/(dB+dU).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061849&req=5

brainsci-03-00460-f010: (A) Polysome profile for nonischemic, sham-operated controls (NIC) CA1. Westerns of fractions for ribosomal proteins S6 and L7a, marking 40S and 60S subunits, respectively. eIF4E is translation initiation factor 4E. Boxes mark polysome-bound (B) and unbound (U) fractions. (B) Gene distances for CA1 and CA3 polysome bound (dB) and polysome-unbound (dU) fractions. (C) gene expression dynamics inspector (GEDI) analysis of microarray 8hR/NIC (R/N) class comparisons. S ~ dB/(dB+dU).
Mentions: Our experimental groups were microdissected hippocampal CA1 and CA3 at 8hR in rat, and in NICs. There were n = 15 animals in each group. Homogenates from 5 animals per group were randomly pooled to give 3 replicates per group. Pooling was necessary to provide enough material to prepare polysome profiles by gradient centrifugation. RNA was extracted from: (1) polysome-containing fractions (polysome-bound mRNAs, B), and (2) the light gradient fractions that did not contain polysomes (polysome unbound, U) (Figure 10A). Next, 24 microarrays were performed for 8 experimental groups (n = 3 microarrays/group): NIC CA1B, NIC CA1U, NIC CA3B, NIC CA3U, 8hR CA1B, 8hR CA1U, 8hR CA3B, and 8hR CA3U.

Bottom Line: We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection.Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery.We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology, Wayne State University, 4116 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA. ddegraci@med.wayne.edu.

ABSTRACT
Our recently described nonlinear dynamical model of cell injury is here applied to the problems of brain ischemia and neuroprotection. We discuss measurement of global brain ischemia injury dynamics by time course analysis. Solutions to proposed experiments are simulated using hypothetical values for the model parameters. The solutions solve the global brain ischemia problem in terms of "master bifurcation diagrams" that show all possible outcomes for arbitrary durations of all lethal cerebral blood flow (CBF) decrements. The global ischemia master bifurcation diagrams: (1) can map to a single focal ischemia insult, and (2) reveal all CBF decrements susceptible to neuroprotection. We simulate measuring a neuroprotectant by time course analysis, which revealed emergent nonlinear effects that set dynamical limits on neuroprotection. Using over-simplified stroke geometry, we calculate a theoretical maximum protection of approximately 50% recovery. We also calculate what is likely to be obtained in practice and obtain 38% recovery; a number close to that often reported in the literature. The hypothetical examples studied here illustrate the use of the nonlinear cell injury model as a fresh avenue of approach that has the potential, not only to solve the brain ischemia problem, but also to advance the technology of neuroprotection.

No MeSH data available.


Related in: MedlinePlus