ISC – FRIDAY NEWS TIP ABSTRACTS
Control:
2748/173 Embargoed for 8:48 a.m. PT/11:48 a.m. ET, Friday, Feb. 11, 2011
Title:
The Efficacy of Human Umbilical Tissue-Derived Cells in Restoring Neurological Function in
an Aged Rat Embolic Stroke Model
Authors:
Klaudyne Hong, Michael Romanko, Anna Gosiewska, ATRM, Somerville, NJ; Yi Li, Michael
Chop, Dept of Neurology, Henry Ford Hosp, Detroit, MI
Disclosures: K. Hong: Employment; Significant; Klaudyne Hong is an employee of ATRM. M.
Romanko: Michael Romanko is an employee of ATRM. A. Gosiewska: Anna Gosiewska is
an employee of ATRM. Y. Li: None. M. Chop: None.
Category:
Basic and Translational Neuroscience of Stroke Recovery
Abstract:
Background: In view of the limited treatment options for stroke patient, significant research
has focused on novel therapeutic approaches. The effectiveness of these novel treatments needs
to be confirmed in relevant animal models prior to clinical evaluation. The aged rat embolic
stroke model creates a relatively challenging preclinical setting to test new therapies. This
model is particularly relevant to mimic a disease that strikes mostly senior individuals. In this
study, the effectiveness of human umbilical tissue-derived cells (hUTC) is evaluated in the
aged rat embolic stroke model.
Method: Sixteen 20-month old, 500-g Wistar rats underwent right middle cerebral artery
(MCA) occlusion by placement of a 24-hr old fibrin-rich clot. Animals were then randomly
assigned to 2 groups: Group 1 was injected with 10 million hUTC / kg body weight; Group 2
was injected with vehicle only. Both Groups were treated 1 day post-stroke. All rats received
injections of 5-Bromo-2-deoxyuridine (50mg/kg body weight) for 14 consecutive days starting
24 hrs post-stroke to allow assessment of cell proliferation in the ischemic area of the brain.
The functional neurobehavioral tests were assessed weekly: modified neurological severity
score (mNSS), foot-fault, and adhesive removal tests. Animals were sacrificed on day 60.
Histological assessments included infarct area measurement, immunohistochemical analyses to
evaluate cell proliferation, cell death, and new vessels and synapses formation.
Results: Group 1(receiving hUTC) demonstrated significant improvement in neurological
function as evaluated by mNSS, foot fault, and adhesive removal tests, as compared to Group 2
(receiving vehicle). The significant functional improvement was observed as early as one
month following treatment and was maintained for 60 days after embolic stroke. Histological
analysis showed no significant differences in lesion volume, cell proliferation or cell death
between groups. Histological analyses of Group 1 exhibited significant increases in the number
of microvessels and synaptophysin expression in the ipsilateral hemisphere compared to Group
2.
Conclusion: The intravenous injection of 10 million hUTC/ kg body weight at one day poststroke in an aged rodent embolic stroke model resulted in significant neurological improvement
vs. injection of control, vehicle only, along with histological evidence of increased
angiogenesis and synaptogenesis in the area of the ischemic boundary zone. These promising
results prompt further research towards clinical effectiveness.
Control:
2440/169 Embargoed for 8 a.m. PT/11 a.m. ET, Friday, Feb. 11, 2011
Title:
Amount But Not Pattern Of Protective Peripheral Stimulation Affects The Complete
Recovery Of Cortical Function Following Permanent Middle Cerebral Artery Occlusion
Authors:
Melissa F Davis, Christopher C Lay, Cynthia Chen-Bee, Ron D Frostig, Univeristy of
Califorina- Irvine, Irvine, CA
Disclosures: M.F. Davis: None. C.C. Lay: None. C. Chen-Bee: None. R.D. Frostig: None.
Category: Basic and Translational Neuroscience of Stroke Recovery
Abstract:
Using a rodent model of ischemia (pMCAO; permanent middle cerebral artery occlusion),
our lab has previously demonstrated that 120 minutes of patterned, intermittent stimulation
of a single whisker, initiated within a two-hour window following pMCAO, can fully protect
the cortex from impending damage via initiation of collateral flow. The same whisker
stimulation however, when initiated three hours post-pMCAO, causes an irreversible loss of
function and cortical infarct. These conclusions were based on functional imaging, neuronal
recording, blood flow imaging, histological assessment, and behavioral analyses (Lay et al.,
PLoS ONE, 2010). In the current study we assessed the hypothesis that the ability of this
treatment to protect is dependent upon the amount of stimulation delivered but not on its
pattern of delivery. To test this hypothesis we administered the same whisker stimulation as
used in the previous study, but at random rather than patterned intervals and condensed into
the first 10 minutes or spread out over the first 2 hours following pMCAO. We also tested
whether an increase in the amount of whiskers stimulated (entire whisker set versus a single
whisker) could accelerate the recovery of evoked function previously observed. Utilizing
Intrinsic Signal Optical Imaging (ISOI) and 2,3,5-triphenultetrazolium chloride (TTC)
staining we assessed the cortex for functional viability and stained for infarct. Randomized
whisker stimulation (whether condensed or dispersed) resulted in protection equivalent to
patterned whisker stimulation; animals had pre-pMCAO functional responses by the
following day and sustained no infarct. We also found that entire-whisker-set stimulation
resulted in equivalent protection and lack of infarct, but promoted faster recovery of evoked
functional responses (30 minutes faster; F1,15=14.22, p<.005). If not initiated until three
hours post-pMCAO, however, entire-whisker-set stimulation resulted not only in loss of
evoked function, but in infarct volumes significantly larger than those sustained by single
whisker counterparts. These findings suggest that the ability of sensory stimulation to
completely protect the cortex from ischemic damage is not sensitive to changes in duration
or pattern of stimulation and that more stimulation is more beneficial- as long as it is
administered early. Taken together, this suggests that stimulus-evoked cortical activity,
irrespective of the parameters of peripheral stimulation that initiated it, is the key factor in
the observed protection. Further, these results, if translational, point towards a non-invasive
treatment which could be administered before arrival to the hospital and could therefore add
to the armamentarium of clinical stroke treatment options. Supported by (NIH-NINDS) NS55832.
Control:
2115/170 Embargoed for 8:12 a.m. PT/11:12 a.m. ET, Friday, Feb. 11, 2011
Title:
Docosahexaenoic Acid Rescues The Penumbra After Ischemic Stroke In Rats
Authors:
Ludmila Belayev, Larissa Khoutorova, Kristal D. Atkins, Tiffany D Eady, LOUISIANA
STATE UNIVERSITY, New Orleans, LA; Andre Obenaus, Loma Linda Univ, Loma Linda,
CA; Nicolas G Bazan, LOUISIANA STATE UNIVERSITY, New Orleans, LA
Disclosures: L. Belayev, None; L. Khoutorova, None; K.D. Atkins, None; T.D. Eady, None; A. Obenaus,
None; N.G. Bazan, None.
Category:
Basic and Translational Neuroscience of Stroke Recovery
Abstract:
Background and Purpose: Docosahexaenoic acid (DHA; 22:6n-3), an omega-3 essential fatty
acid family member, is the precursor of neuroprotectin D1, which downregulates apoptosis and
promotes cell survival. Recently, we have shown that DHA therapy in low and medium doses
improves outcome following focal cerebral ischemia. We used magnetic resonance imaging
(MRI) and mass spectrometry in conjunction with behavioral, histological and immunostaining
methods to study DHA action after stroke.
Methods: In each series described below, SD rats underwent 2 h of MCAo. In series 1
(therapeutic window study), DHA or saline was administered i.v. at either 3, 4, 5, or 6 h after
onset of stroke. Behavioral testing was conducted on days 1, 2, 3 and 7 followed by
histopathology on day 7. In series 2 (MRI study), DHA or saline was administered at 3 h after
onset of stroke and MRI was conducted on days 1, 3 and 7. In series 3 (lipidomic study), DHA
or saline was administered at 3 h, and then brains were sectioned into penumbral and core
regions and underwent mass spectrometry lipidomic analysis on day 3.
Results. Treatment with DHA significantly improved behavior on days 1, 2 3 and 7 and
significantly reduced total infarct volume by a mean of 40% when administered at 3 h; by 66%
at 4 h; and by 59% at 5 h. In addition, numbers of the GFAP-positive reactive astrocytes and
ED-1-positive microglia/macrophages were reduced by DHA treatment. In the MRI study,
initial smaller infarcts were only localized to the striatum on day 1 and were indistinguishable
from normal tissues by day 7 in DHA-treated rats. DHA yielded reduced T2 values (decreased
edema) in the lesion and 3D infarct volumes (computed from T2WI) at all time points, and there
were no differences in T2 values for the contralateral tissues. There was a difference in the ADC
(apparent diffusion coefficient) within the infarcted lesion when comparing saline and DHA rats
at days 1, 3 and 7 after MCAo. Lipidomic analysis showed that DHA treatment potentiates
NPD1 synthesis in the penumbra 3 days after MCAo.
Conclusions: We have shown that DHA administration provides neurobehavioral recovery,
reduces brain infarction and brain edema, activates neuroprotectin D1 synthesis in the
penumbra, and promotes cell survival when administered up to 5 h after focal cerebral ischemia
in rats.