Publications by authors named "Alexander Mdzinarishvili"

11 Publications

  • Page 1 of 1

The Mitochondrial mitoNEET Ligand NL-1 Is Protective in a Murine Model of Transient Cerebral Ischemic Stroke.

Pharm Res 2021 May 12;38(5):803-817. Epub 2021 May 12.

Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, West Virginia, 26506, USA.

Purpose: Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method: In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

Results: NL-1 decreased hydrogen peroxide production with an IC of 5.95 μM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%.

Conclusion: As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.
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http://dx.doi.org/10.1007/s11095-021-03046-4DOI Listing
May 2021

PET Detection of Cerebral Necrosis Using an Infarct-Avid Agent 2-Deoxy-2-[F]Fluoro-D-Glucaric Acid (FGA) in a Mouse Model of the Brain Stroke.

Mol Imaging Biol 2020 10;22(5):1353-1361

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, 1110 N. Stonewall Ave, Oklahoma City, OK, 73117, USA.

Purpose: Ischemic stroke is a leading cause of disability worldwide. The volume of necrotic core in affected tissue plays a major role in selecting stroke patients for thrombolytic therapy or endovascular thrombectomy. In this study, we investigated a recently reported positron emission tomography (PET) agent 2-deoxy-2-[F]fluoro-D-glucaric acid (FGA) to determine necrotic core in a model of transient middle cerebral artery occlusion (t-MCAO) in mice.

Procedures: The radiopharmaceutical, FGA, was synthesized by controlled, rapid, and quantitative oxidation of clinical doses of 2-deoxy-2-[F]fluoro-D-glucose (FDG) in a one-step reaction using a premade kit. Brain stroke was induced in the left cerebral hemisphere of CD-1 mice by occluding the middle cerebral artery for 1 h, and then allowing reperfusion by removing the occlusion. One day post-ictus, perfusion single-photon emission tomography (SPECT) was performed with Tc-lableled hexamethylpropyleneamine oxime (HMPAO), followed by PET acquisition with FGA. Plasma and brain tissue homogenates were assayed for markers of inflammation and neurotrophins.

Results: The kit-based synthesis was able to convert up to 2.2 GBq of FDG into FGA within 5 min. PET images showed 375 % more accumulation of FGA in the ipsilateral hemisphere than in the contralateral hemisphere. SPECT images showed that the ipsilateral HMPAO accumulation was reduced to 55 % of normal levels; there was a significant negative correlation between the ipsilateral accumulation of FGA and HMAPO (p < 0.05). FGA accumulation in stroke also correlated with IL-6 levels in the ipsilateral hemisphere. There was no change in IL-6 or TNFα in the plasma of stroke mice.

Conclusions: Accumulation of FGA correlated well with the perfusion defect and inflammatory injury. As a PET agent, FGA has potential to image infarcted core in the brain stroke injury with high sensitivity, resolution, and specificity.
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http://dx.doi.org/10.1007/s11307-020-01513-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494640PMC
October 2020

Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: Possible association with AQP4 modulation.

J Neurol Sci 2015 Jul 1;354(1-2):37-45. Epub 2015 May 1.

Department of Rehabilitation Sciences, College of Allied Health, The University of Oklahoma, Health Sciences Center, Oklahoma City, OK 73117-1215, USA. Electronic address:

The use of neuroprotective strategies to mitigate the fatal consequences of ischemic brain stroke is a focus of robust research activity. We have previously demonstrated that thyroid hormone (T3; 3,3',5-triiodo-l-thyronine) possesses neuroprotective and anti-edema activity in pre-stroke treatment regimens when administered as a solution or as a nanoparticle formulation. In this study we have extended our evaluation of thyroid hormone use in animal models of brain stroke. We have used both transient middle cerebral artery occlusion (t-MCAO) and permanent (p-MCAO) models of ischemic brain stroke. A significant reduction of tissue infarction and a concurrent decrease in edema were observed in the t-MCAO model of brain stroke. However, no benefit of T3 was observed in p-MCAO stroke setting. Significant improvement of neurological outcomes was observed upon T3 treatment in t-MCAO mice. Further, we tested T2 (3,5-diiodo-l-thyronine) a natural deiodination metabolite of T3 in MCAO model of brain stroke. T2 potently decreased infarct size as well as edema formation. Additionally, we report here that T3 suppresses the expression of aquaporin-4 (AQP4) water channels which could be a likely mechanism of its anti-edema activity. Our studies provide evidence to stimulate clinical development of thyroid hormones for use in ischemic brain stroke.
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http://dx.doi.org/10.1016/j.jns.2015.04.042DOI Listing
July 2015

Engineering triiodothyronine (T3) nanoparticle for use in ischemic brain stroke.

Drug Deliv Transl Res 2013 Aug;3(4):309-17

Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH 44272 USA.

A potential means of pharmacological management of ischemic stroke is rapid intervention using potent neuroprotective agents. Thyroid hormone (T3) has been shown to protect against ischemic damage in middle cerebral artery occlusion (MCAO) model of ischemic brain stroke. While thyroid hormone is permeable across the blood-brain barrier, we hypothesized that efficacy of thyroid hormone in ischemic brain stroke can be enhanced by encapsulation in nanoparticulate delivery vehicles. We tested our hypothesis by generating poly-(lactide-co-glycolide)-polyethyleneglycol (PLGA-b-PEG) nanoparticles that are either coated with glutathione or are not coated. We have previously reported that glutathione coating of PLGA-PEG nanoparticles is an efficient means of brain targeted drug delivery. Encapsulation of T3 in PLGA-PEG delivery vehicle resulted in particles that were in the nano range and exhibited a zeta potential of -6.51 mV (uncoated) or -1.70 mV (coated). We observed that both glutathione-coated and uncoated nanoparticles are taken up in cells wherein they stimulated the expression of thyroid hormone response element driven reporter robustly. In MCAO model of ischemic stroke, significant benefit of administering T3 in nanoparticulate form was observed over injection of a T3 solution. A 34 % decrease in tissue infarction and a 59 % decrease in brain edema were seen upon administration of T3 solution in MCAO stroke model. Corresponding measurements for uncoated T3 nanoparticles were 51 % and 68 %, whereas for the glutathione coated were 58 % and 75 %. Our study demonstrates that using nanoparticle formulations can significantly improve the efficacy of neuroprotective drugs in ischemic brain stroke.
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http://dx.doi.org/10.1007/s13346-012-0117-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693440PMC
August 2013

Ginkgo extract EGb761 confers neuroprotection by reduction of glutamate release in ischemic brain.

J Pharm Pharm Sci 2012 ;15(1):94-102

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center,Amarillo, Texas, USA.

Purpose: Ginkgo extract EGb761 has shown anti-edema and anti-ischemic effects in various experimental models. In the present study, we demonstrate neuroprotective effects of EGb761 in experimental stroke while monitoring brain metabolism by microdialysis.

Methods: We have used oxygen-glucose deprivation in brain slices in vitro and middle cerebral artery occlusion (MCAO) in vivo to induce ischemia in mouse brain. We used microdialysis in mouse striatum to monitor extracellular concentrations of glucose and glutamate.

Results: In vitro, EGb761 reduced ischemia-induced cell swelling in hippocampal slices by 60%. In vivo, administration of EGb761 (300 mg/kg) reduced cell degeneration and edema formation after MCAO by 35-50%. Immediately following MCAO, striatal glucose levels dropped to 25% of controls, and this reduction was not significantly affected by EGb761. Striatal glutamate levels, in contrast, increased 15-fold after MCAO; after pretreatment with EGb761, glutamate levels only increased by 4-5fold.

Conclusions: We show that pretreatment with EGb761 strongly reduces cellular edema formation and neurodegeneration under conditions of ischemia. The mechanism of action seems to be related to a reduction of excitotoxicity, because ischemia-induced release of glutamate was strongly suppressed. Ginkgo extracts such as EGb761 may be valuable to prevent ischemia-induced damage in stroke-prone patients.
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http://dx.doi.org/10.18433/j3ps37DOI Listing
May 2012

Neuroprotective effects of bilobalide are accompanied by a reduction of ischemia-induced glutamate release in vivo.

Brain Res 2011 Nov 6;1425:155-63. Epub 2011 Oct 6.

Department of Pharmacology, College of Pharmacy, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.

Neuroprotective properties of bilobalide, a specific constituent of Ginkgo extracts, were tested in a mouse model of stroke. After 24h of middle cerebral artery occlusion (MCAO), bilobalide reduced infarct areas in the core region (striatum) by 40-50% when given at 10mg/kg 1h prior to MCAO. Neuroprotection was also observed at lower doses, or when the drug was given 1h past stroke induction. Sensorimotor function in mice was improved by bilobalide as shown by corner and chimney tests. When brain metabolism in situ was monitored by microdialysis, MCAO caused a rapid disappearance of extracellular glucose in the striatum which returned to baseline levels after reperfusion. Extracellular levels of glutamate were increased by more than ten-fold in striatal tissue, and by four- to fivefold in hippocampal tissue (penumbra). Bilobalide did not affect glucose levels but strongly attenuated glutamate release in both core and penumbra regions. Bilobalide was equally active when given locally via the microdialysis probe and also reduced ischemia-induced glutamate release in vitro in brain slices. We conclude that bilobalide is a strong neuroprotectant in vivo at doses that can be used therapeutically in humans. The mechanism of action evidently involves reduction of glutamate release, thereby reducing excitotoxicity.
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http://dx.doi.org/10.1016/j.brainres.2011.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217178PMC
November 2011

Metabolic and transmitter changes in core and penumbra after middle cerebral artery occlusion in mice.

Brain Res 2010 Feb 2;1312:101-7. Epub 2009 Dec 2.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Center, 1300 Coulter Dr, Amarillo, TX 79106, USA.

Middle cerebral artery occlusion (MCAO) is a popular model in experimental stroke research and causes prominent ischemic damage in the forebrain. To characterize metabolic changes induced by MCAO, we have induced permanent MCAO in mice that were implanted with a microdialysis probe in either striatum or hippocampus. Immediately after the onset of ischemia, glucose levels dropped to <10% of basal values in the striatum while they dropped to 50%, and recovered thereafter, in hippocampus. Extracellular levels of glutamate rose 80-fold in the striatum but only 10-fold, and in a transient fashion, in hippocampus. In striatum, release of acetylcholine briefly increased, then dropped to very low values. Both glycerol and choline levels increased strongly during ischemia in the striatum reflecting membrane breakdown. In hippocampus, glycerol increased transiently while the increase of choline levels was moderate. Taken together, these observations delineate metabolic changes in ischemic mouse brain with the striatum representing the core area of ischemia. In comparison, the dorsal hippocampus was identified as a brain area suitable for monitoring metabolic responses in the penumbra region.
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http://dx.doi.org/10.1016/j.brainres.2009.11.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812654PMC
February 2010

Nicotine exacerbates brain edema during in vitro and in vivo focal ischemic conditions.

J Pharmacol Exp Ther 2010 Feb 4;332(2):371-9. Epub 2009 Nov 4.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University, Health Sciences Center, Amarillo, Texas, USA.

We have previously shown that nicotine, the addictive component of tobacco products, alters the blood-brain barrier (BBB) Na(+),K(+),2Cl(-) cotransporter (NKCC) during in vitro hypoxia-aglycemia exposure. Attenuation of abluminal NKCC suggests that accumulation of ions in the brain extracellular fluid would result in an increase of fluid or cytotoxic edema in the brain during hypoxia-aglycemia or stroke conditions. To further investigate whether nicotine products have the potential to worsen stroke outcome by increasing edema formation, two separate models to mimic stroke conditions were utilized to decipher the effects of short-term and long-term administrations of nicotine products on brain edema following stroke. Oxygen glucose deprivation (OGD) was studied in rat hippocampal slices with short-term or long-term exposure to nicotine and cigarette smoke constituents. During short-term exposure, the presence of nicotine at a concentration mimicking heavy smokers increased water content of hippocampal slices during OGD. Furthermore, long-term 1-week administration of nicotine increased water content in hippocampal slices that could be attenuated with nicotine acetylcholine receptor (nAChR) antagonists, suggesting nicotine increase edema during OGD via nAChRs. A second model of focal ischemia, middle cerebral artery occlusion, showed an increase of infarct size during short-term exposure to nicotine and an increase of edema during both short-term and long-term administration of nicotine, compared with saline controls. These findings support the paradigm that nicotine products not only increase the incidence of stroke but also have the potential to worsen stroke outcome by increased edema formation.
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http://dx.doi.org/10.1124/jpet.109.157776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812118PMC
February 2010

Neuroprotection in mice by NGP1-01 after transient focal brain ischemia.

Brain Res 2008 Feb 29;1196:113-20. Epub 2008 Jan 29.

Department of Pharmaceutical Sciences and PATOS Stroke Research Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.

The effect of the polycyclic cage amine NGP1-01, a dual action antagonist at both L-type calcium channels and NMDA receptors, was measured after transient (1 h) focal cerebral ischemia in the mouse middle cerebral artery occlusion (MCAO) model. Mice were left untreated, or received NGP1-01 (20 mg/kg per dose intraperitoneally), memantine (20 mg/kg per dose intraperitoneally), or vehicle (DMSO) at 15 min, 24 h and 48 h after reperfusion. Sensorimotor function was tested daily for two weeks using the "corner test", a proven paradigm for the assessment of functional integrity in rodents. NGP1-01 significantly reduced sensorimotor deficits over the 2-week period (p<0.001, ANOVA). Although memantine was less effective than NGP1-01 (p<0.05), it still significantly attenuated sensorimotor deficits in the animals. In a separate study, brain damage 3 days after stroke was determined histologically in mice receiving no treatment, DMSO, or NGP1-01 (dosages and dosage schedule same as above). Serial brain sections were stained for nonviable neurons with Fluoro-Jade B and the volume of damaged tissue was estimated. NGP1-01 treated mice had a significantly lower volume of brain damage (13+/-7 mm(3), p<0.01) than both control groups (no treatment: 47+/-4 mm(3), DMSO: 50+/-10 mm(3)). In conclusion, at weight-equivalent doses, NGP1-01 was at least as neuroprotective as the established NMDA receptor antagonist memantine. It may be a promising lead structure for the development of novel multiple-action drugs in treating ischemic stroke and other neurodegenerative diseases with an excitotoxic component.
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http://dx.doi.org/10.1016/j.brainres.2007.11.075DOI Listing
February 2008

NMDA receptor-antagonistic properties of hyperforin, a constituent of St. John's Wort.

J Pharmacol Sci 2006 Sep 26;102(1):47-54. Epub 2006 Aug 26.

Department of Pharmaceutical Sciences and Collaborative Stroke Center, Texas Tech School of Pharmacy, USA.

Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of affective disorders. Hyperforin, a constituent of St. John's wort, is known to modulate the release and re-uptake of various neurotransmitters, an action that likely underlies its antidepressive activity. We now report that hyperforin also has N-methyl-D-aspartate (NMDA)-antagonistic effects. Hyperforin (10 microM) was found to inhibit the NMDA-induced calcium influx into cortical neurons. In rat hippocampal slices, hyperforin inhibited the NMDA-receptor-mediated release of choline from phospholipids. Hyperforin also antagonized the increase of water content in freshly isolated hippocampal slices, and it counteracted, at 3 and 10 microM, the increase of water content induced by NMDA. Hyperforin was inactive, however, in two in vivo models of brain edema formation, middle cerebral artery occlusion and water intoxication in mice. In conclusion, hyperforin has NMDA-receptor-antagonistic and potential neuroprotective effects in vitro. This effect may contribute to the therapeutic effectiveness of St. John's wort extracts in some situations, for example, for relapse prevention in alcoholism.
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http://dx.doi.org/10.1254/jphs.fp0060378DOI Listing
September 2006

NGP1-01, a lipophilic polycyclic cage amine, is neuroprotective in focal ischemia.

Neurosci Lett 2005 Jul 22-29;383(1-2):49-53. Epub 2005 Apr 13.

Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University HSC, Amarillo, 79106-1712, USA.

NGP1-01, a member of the pentacycloundecylamine cage compound family, was recently shown to exhibit both NMDA receptor channel blocking and L-type calcium channel antagonism activity. In the present study, focal ischemia was induced in mice by permanent middle cerebral artery occlusion (MCAO) to test for potential neuroprotective properties of the compound. In female CD-1 mice injected 30 min before MCAO, NGP1-01 (20 mg/kg) reduced infarct area by 42.6% (P < 0.05) compared to vehicle-treated controls as visualized by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Concomitantly, NGP1-01 reduced brain swelling by 78.3% (P < 0.001), compared to vehicle (DMSO) treated controls. These data identify NGP1-01 and related compounds as potential lead structures to develop neuroprotective compounds based on a dual mechanism of action.
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http://dx.doi.org/10.1016/j.neulet.2005.03.042DOI Listing
August 2005