Jouko A. Lukkarinen

University of Kuopio, Kuopio, Eastern Finland Province, Finland

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Publications (16)58.79 Total impact

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    ABSTRACT: The ability of on-resonance T(1rho) (T(1rho)) and off-resonance T(1rho) (T(1rho)(off)) measurements to indicate acute cerebral ischemia in a rat model of transient middle cerebral artery (MCA) occlusion was investigated at 4.7 T. T(1rho) was determined with B(1) fields of 0.4, 0.8, and 1.6 G, and T(1rho)(off) with five offset frequencies ((Delta)omega) ranging from 0-7.5 kHz at B(1) of 0.4 G, yielding effective B(1) (B(eff)) from 0.4 to 1.8 G. Diffusion, T(1), and T(2) were also quantified. Both T(1rho) and T(1rho)(off) acquired with (Delta)(o)< 2.5 kHz showed positive contrast during the first hours of MCA occlusion in the ischemic tissue delineated by low diffusion. Interestingly, T(1rho)(off) contrast acquired with (Delta)omega > 2.5 kHz was clearly less sensitive to ischemic alterations, and developed with a delayed time course. This discrepancy is thought to be a consequence of the frequency dependency of cross-relaxation during irradiation with spin-lock pulses.
    Magnetic Resonance in Medicine 01/2003; 49(1):172-6. DOI:10.1002/mrm.10356 · 3.57 Impact Factor
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    ABSTRACT: Activation of the gamma-amino butyric acid (GABA)-ergic system might protect against the damage that occurs after cerebral ischaemia. We examined this hypothesis by administering diazepam to rats subjected to transient middle cerebral artery occlusion (MCAO) using the intraluminal thread method. Diffusion MRI (DWI) and perfusion imaging (PI) were acquired during MCAO to assess brain tissue status and haemodynamics, respectively. Rats were intraperitoneally injected with either 10 mg kg(-1) diazepam (n = 5) or vehicle (n = 5) both 30 min and 90 min after the onset of MCAO. To exclude the possibility that neuroprotection was due to the hypothermic action of the drug, body temperature was maintained at 37-38 degrees C for up to 7 h postischaemia with a feed-back controlled thermoregulatory unit. Infarct volumes quantified 2 days after MCAO from T(2)-weighted images were similar in ischaemic control rats and in ischaemic rats treated with diazepam. We conclude that diazepam-induced enhancement of GABA(A) activity does not effectively protect against neuronal damage that occurs after transient MCAO in normothermic rats.
    Journal of Pharmacy and Pharmacology 12/2002; 54(11):1565-9. DOI:10.1211/002235702180 · 2.26 Impact Factor
  • S Butovas · J Lukkarinen · T Virtanen · J Jolkkonen · J Sivenius ·
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    ABSTRACT: Tbc present study compared tbc effect of chronic administration of the selective alpha2-adrenoceptor antagonist, atipamezole, on performance in behavioral tests that differ in motoric complexity in two experimental stroke models. Transient occlusion (120 min) of the middle cerebral artery (MCA) using the intraluminal method was used to produce corticostriatal infarcts and permanent occlusion of distal MCA by electrocoagulation was used to produce cortical infarcts. Chronic atipamezole treatment (1 mg/kg, s.c., once per day) was started 2 days after ischemia induction and continued until the end of the experiment, 35 days after ischemia induction. Behavioral performance of the operated rats was assessed 30 min after drug administration using the limb-placing test and Montoya's staircase test. Atipamezole facilitated spontaneous recovery in the limb-placing task particularly in rats subjected to transient MCA occlusion. The analysis of retrieved pellets in Montoya's staircase test suggests that there is no recovery (Time effect, P > 0.05) in the use of the impaired forelimb (contralateral-to-lesion) following transient MCA occlusion, whereas there was some recovery following permanent MCA occlusion (Time effect, P < 0.001). The impairment was bilateral in rats subjected to transient MCA occlusion. Atipamezole treatment did not affect the use of the impaired forelimb to retrieve pellets following transient MCA occlusion, but there was a tendency to facilitate impaired forelimb use following permanent MCA occlusion (Time*Treatment interaction, P = 0.086). Transient occlusion of the MCA produced a severe, long lasting, and bilateral deficit in skilled forelimb use. Permanent occlusion of the distal MCA was associated with less severe impairment, which was alleviated to some extent by administration of atipamezole. This is in contrast to spontaneous recovery and recovery-enhancing effects of atipamezole in the limb-placing test, particularly in the transient MCA occlusion model.
    Restorative neurology and neuroscience 02/2001; 18(4):143-51. · 2.49 Impact Factor
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    ABSTRACT: Interrelation of T(1) and diffusion of water was studied in rat models of acute global and focal cerebral ischemia. Cortical T(1), as quantified with an inversion recovery method, increased by 4-7% within a few minutes of global ischemia at 4.7 and 9.4 T, but a significantly smaller change was detected at 1.5 T. The initial T(1) change occurred within seconds of cardiac arrest, much earlier than the extensive diffusion drop after 1-2 min. Thus, the initial increase in T(1) upon acute cerebral ischemia is directly caused by cessation of blood flow. In transient middle cerebral artery occlusion (MCAO), prolonged T(1) relaxation was detected within 10 min, with a subsequent increase during the course of ischemia. Spin density did not change during the first hour, showing that T(1) increase was not caused by net accumulation of water. Interestingly, partial recovery of T(1) upon release of MCAO, occurring independent of long-term tissue outcome, was observed only in concert with diffusion recovery.
    Magnetic Resonance in Medicine 01/2001; 44(6):833-9. · 3.57 Impact Factor
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    ABSTRACT: Interrelation of T1 and diffusion of water was studied in rat models of acute global and focal cerebral ischemia. Cortical T1, as quantified with an inversion recovery method, increased by 4–7% within a few minutes of global ischemia at 4.7 and 9.4 T, but a significantly smaller change was detected at 1.5 T. The initial T1 change occurred within seconds of cardiac arrest, much earlier than the extensive diffusion drop after 1–2 min. Thus, the initial increase in T1 upon acute cerebral ischemia is directly caused by cessation of blood flow. In transient middle cerebral artery occlusion (MCAO), prolonged T1 relaxation was detected within 10 min, with a subsequent increase during the course of ischemia. Spin density did not change during the first hour, showing that T1 increase was not caused by net accumulation of water. Interestingly, partial recovery of T1 upon release of MCAO, occurring independent of long-term tissue outcome, was observed only in concert with diffusion recovery. Magn Reson Med 44:833–839, 2000. © 2000 Wiley-Liss, Inc.
    Magnetic Resonance in Medicine 12/2000; 44(6):833 - 839. DOI:10.1002/1522-2594(200012)44:6<833::AID-MRM3>3.0.CO;2-F · 3.57 Impact Factor
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    ABSTRACT: The impact of brain imaging on the assessment of tissue status is likely to increase with the advent of treatment methods for acute cerebral ischemia. Multimodal magnetic resonance imaging (MRI) demonstrates potential for selecting stroke therapy patients by identifying the presence of acute ischemia, delineating the perfusion defect, and excluding hemorrhage. Yet, the identification of tissue subject to reversible or irreversible ischemia has proven to be difficult. Here, the authors show that T1 relaxation time in the rotating frame, so-called T1rho, serves as a sensitive MRI indicator of cerebral ischemia in the rat. The T1rho prolongs within minutes after a drop in the CBF of less than 22 mL 100 g(-1) min(-1). Dependence of T1rho on spin-lock amplitude, termed as T1rho dispersion, increases by approximately 20% on middle cerebral artery (MCA) occlusion, comparable with the magnitude of diffusion reduction. The T1rho dispersion change dynamically increases to be 38% +/- 10% by the first 60 minutes of ischemia in the brain region destined to develop infarction. Following reperfusion after 45 minutes of MCA occlusion, the tissue with elevated T1rho dispersion (yet normal diffusion) develops severe histologically verified neuronal damage; thus, the former parameter unveils an irreversible condition earlier than currently available MRI methods. The T1rho dispersion as a novel MRI index of cerebral ischemia may be useful in determination of the therapeutic window for acute ischemic stroke.
    Journal of Cerebral Blood Flow & Metabolism 11/2000; 20(10):1457-66. DOI:10.1097/00004647-200010000-00007 · 5.41 Impact Factor
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    ABSTRACT: It has been suggested that the increased production of endogenous BDNF after brain insults supports the survival of injured neurons and limits the spread of the damage. In order to test this hypothesis experimentally, we have produced transgenic mouse lines that overexpress the dominant-negative truncated splice variant of BDNF receptor trkB (trkB.T1) in postnatal cortical and hippocampal neurons. When these mice were exposed to transient focal cerebral ischemia by occluding the middle cerebral artery for 45 min and the damage was assessed 24 h later, transgenic mice had a significantly larger damage than wild-type littermates in the cerebral cortex (204 +/- 32% of wild-type, P = 0.02), but not in striatum, where the transgene is not expressed. Our results support the notion that endogenously expressed BDNF is neuroprotective and that BDNF signaling may have an important role in preventing brain damage after transient ischemia.
    Molecular and Cellular Neuroscience 09/2000; 16(2):87-96. DOI:10.1006/mcne.2000.0863 · 3.84 Impact Factor

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    ABSTRACT: Sensitivity of T(1) in the rotating frame (T(1rho)) to both transient cerebral ischemia and cortical hypoperfusion was studied in rats. T(1rho) is believed to probe water in close contact with macromolecules, revealing water spins with restricted rotational mobility relative to bulk water. It is shown that T(1rho) increases within minutes of occlusion, thereby demonstrating it as a new, sensitive indicator of ischemia. After reperfusion at 90 minutes of middle cerebral artery occlusion, T(1rho) remains elevated or increases in tissue destined to neuronal damage but returns to the normal level if no neuronal damage develops within 24 hours. T(1rho) determined during the first 2 hours of reperfusion shows a significant positive correlation with the ultimate neuronal damage score. However, T(1rho) is not affected by acute hypoperfusion. These data show that, by combining three magnetic resonance imaging coefficients, i.e. T(1rho), T(2), and diffusion, viable hypoperfused areas that do not develop neuronal damage within 24 hours can be distinguished correctly from tissue already destined for neuronal damage. Magn Reson Med 42:268-276, 1999.
    Magnetic Resonance in Medicine 09/1999; 42(2):268-76. DOI:10.1002/(SICI)1522-2594(199908)42:23.3.CO;2-1 · 3.57 Impact Factor
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    ABSTRACT: Ornithine decarboxylase (ODC) transgenic and alpha-difluoromethyl ornithine (DFMO)-treated rats were exposed to transient middle cerebral occlusion (MCAO) to examine the role of intraischaemic ODC-activity on the evolution of ischaemia-reperfusion damage. Magnetic resonance imaging (MRI) data show that the damage develops slower in ODC transgenic than in DFMO-treated rats, which is not caused by a difference in perfusion. Furthermore, infarct volumes are smaller in the former animals one day later. These data support the idea of endogenous neuroprotective action of ODC.
    Brain Research 06/1999; 826(2):325-9. DOI:10.1016/S0006-8993(99)01327-X · 2.84 Impact Factor
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    ABSTRACT: The hypothesis was tested that hypoperfused brain regions, such as the ischemic penumbra, are detectable by reductions in absolute transverse relaxation time constant (T2) using magnetic resonance imaging (MRI). To accomplish this, temporal evolution of T2 was measured in several models of hypoperfusion and focal cerebral ischemia in the rat at 9.4 T. Occurrence of acute ischemia was determined through the absolute diffusion constant D(av) = 1/3 TraceD, while perfusion was assessed by dynamic contrast imaging. Three types of regions at risk of infarction could be distinguished: (1) areas with reduced T2 (4% to 15%, all figures relative to contralateral hemisphere) and normal D(av), corresponding to hypoperfusion without ischemia; (2) areas with both reduced T2 (4% to 12%) and D(av) (22% to 49%), corresponding to early hypoperfusion with ischemia; (3) areas with increased T2 (2% to 9%) and reduced D(av) (28% to 45%), corresponding to irreversible ischemia. In the first two groups, perfusion-deficient regions detected by bolus tracking were similar to those with initially reduced T2. In the third group, bolus tracking showed barely detectable arrival of the tracer in the region where D(av) was reduced. We conclude that T2 reduction in acute ischemia can unambiguously identify regions at risk and potentially discriminate between reversible and irreversible hypoperfusion and ischemia.
    Journal of Cerebral Blood Flow & Metabolism 09/1998; 18(8):911-20. DOI:10.1097/00004647-199808000-00012 · 5.41 Impact Factor
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    ABSTRACT: Nuclear magnetic resonance imaging (MRI) was used to study dynamics of maturation and the size of ischaemic stroke lesions in rats with greatly increased activity of ornithine decarboxylase (ODC). Syngenic rats, either with or without chronic pre-ischaemic treatment with an ODC inhibitor, alpha-difluoromethylornithine (DFMO), as well as ODC-overexpressing transgenic rats were subjected either to transient middle cerebral artery (MCA) occlusion or permanent occlusion of the cortical branch of MCA. The two models were chosen to assess the role of ODC activity in damage caused by ischaemia and reperfusion, respectively. Diffusion of water was quantified by means of the trace of the diffusion tensor (D(av) = 1/3 Trace D) to assess the extent of energy failure and cytotoxic oedema, whereas the spin-spin relaxation time (T2) was used as a quantitative indicator of irreversible damage by MRI. Exposure to transient MCA occlusion resulted in significantly smaller stroke lesions in the ODC-overexpressing transgenic (246+/-14 mm3) than in syngenic (320+/-9 mm3) or DFMO-treated (442+/-63 mm3) rats as determined 48 h after the occlusion. The differences in sizes were due to smaller lesions in the cortical tissue (transgenic vs. syngenic) or both in cortical and striatal regions (transgenic vs. DFMO-treated animals). The degree of irreversible oedema was greater in DFMO-treated rats than in syngenic or transgenic animals indicating accelerated development of a permanent damage in the absence of ODC induction. Cortical infarct following permanent MCA occlusion developed faster in the DFMO-treated than in syngenic or transgenic rats as the lesion sizes at 10 h were 26.2+/-4.3 mm3, 14.2+/-2.3 mm3 and 12.3+/-1.9 mm3, respectively. However, the stroke volumes by 48 h were not statistically different in the three animal groups. The present data demonstrate that ODC activation is an endogenous neuroprotective measure in transient cerebral ischaemia.
    European Journal of Neuroscience 07/1998; 10(6):2046-55. DOI:10.1046/j.1460-9568.1998.00216.x · 3.18 Impact Factor

  • Pathophysiology 05/1998; 5:251-251. DOI:10.1016/S0928-4680(98)81276-5
  • Jouko Lukkarinen · Joni M.e Oja · Mikko Turunen · Risto A Kauppinen ·
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    ABSTRACT: The kinetics of glutamate 13C-4 label appearance from D-[1-13C]-glucose and 13C-4 label disappearance from steady state following D-12C-glucose incubation were quantified with 1H-observed, 13C-edited nuclear magnetic resonance (NMR) spectroscopy in the superfused brain slices under largely varying oxygen consumption. Label incorporation to and from glutamate C-4 were fitted into mono- or bicompartmental models in order to determine the respective rate constants and to assess the presence of plausible multiple pools. At a steady-state oxygen consumption of approximately 4 mumol/min/g dry weight, glutamate labelling could be fitted into a biexponential equation, suggesting that there were two compartments with a large difference in their rates (respective rate constants of 0.022 and 0.149) and pool sizes (relative contributions of 91.2 and 8.8%, respectively). Stimulation of oxygen consumption in the brain slice preparations with either 40 mM KCl by 59.5 +/- 10.3% or 5 microM carbonyl cyanide m-fluorophenyl hydrazone by 61.4 +/- 8.4% increased glutamate C-4 labelling rate constants to 0.058 +/- 0.009 and 0.054 +/- 0.006, respectively. In the stimulated slice preparation, glutamate labelling could only be fitted into a monoexponential equation. 13C-4 label disappearance, independent of oxygen uptake, could also only be fitted into a monoexponential equation. There was a close match between the rate constants of label disappearance and appearance in non-stimulated and carbonyl cyanide m-fluorophenyl hydrazone-stimulated slices. In the presence of 40 mM KCl label disappearance did not, however, increase. These data show that glutamate C-4 turnover from exogenous D-[1-13C]-glucose can be used as an index of oxidative metabolism in situ under steady-state conditions as well as when oxygen metabolism is strongly stimulated. The results are discussed with respect to the use of NMR spectroscopy as a means of mapping brain oxidative metabolism.
    Neurochemistry International 08/1997; 31(1):95-104. DOI:10.1016/S0197-0186(96)00120-9 · 3.09 Impact Factor

  • Biological Psychiatry 07/1997; 42(1). DOI:10.1016/S0006-3223(97)88037-7 · 10.26 Impact Factor
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    ABSTRACT: Cerebral ischemia causes activation of ornithine decarboxylase (ODC) gene and subsequent accumulation of putrescine, which might either directly or indirectly affect the outcome of cerebral infarct. We developed a transgenic rat overexpressing human ODC, which was used to explore the effect of abnormally high putrescine concentration in the brain on the infarct volume after permanent middle cerebral artery (MCA) occlusion. The transgenic rats were produced by the pronuclear injection technique with the use of cloned human ODC gene. The right MCA was permanently occluded through craniotomy. ODC activity and polyamines were assayed in the infarcted and contralateral hemispheres. MRI was used to quantify T2 relaxation time, apparent diffusion constant (ADC), and infarct volume, which was also determined by 2,3,5-triphenyltetrazolium chloride. Permanent MCA occlusion resulted in extensive activation of ODC, which was approximately sevenfold greater than in syngenic animals at 20 hours after occlusion. Consequently, putrescine increased from approximately 10 and 230 pmol/mg to 160 and 410 pmol/mg in the infarcted hemisphere of syngenic and transgenic animals, respectively, but all the other polyamines were unchanged. This high putrescine in the transgenic rats did not influence infarct size evolution, as determined by MRI, T2, ADC, or the infarct volume by 2,3,5-triphenyltetrazolium chloride at 48 hours. Data from the ODC transgenic rat model show that the development of brain infarct after permanent MCA occlusion was not influenced by extensive levels of putrescine, indicating that this endogenous amine is not involved in maturation and spread of stroke lesion in vivo. Thus, it seems that ODC activation reflects an endogenous adaptation of neural cells to a noxious stimulus that does not directly influence lesion development.
    Stroke 04/1997; 28(3):639-45. DOI:10.1161/01.STR.28.3.639 · 5.72 Impact Factor