MRI and MRS Studies on the Time Course of Rat Brain Lesions and the Effect of Drug Treatment: Volume Quantification and Characterization of Tissue Hleterogeneity by Parameter Selection zyx Uwe Pschorn, Hermann Korperich, Lothar Heymans, Sankaran Subramanian, Winfried Kuhn zyxwvu Ma(gnetic resonance imaging has been used to follow the time coiirse of lesions induced in the rat brain as an animal model for characterization of the volume of the lesion. The disper- sion in spin-spin relaxation has been used to characterize the nature of the brain lesion. Parameter selective estimation of zyxwvut T,, quantitative determination of the lesion sire and volume seilective in vivo proton spectroscopy have been employed for the purpose. The work has been carried out on rats which weire subject to lesionlng by ibotenlc acid as a model for exc:ltotoxiclty and also on rats which received doses of ibotenic acid and subsequent doses of the NMDA antagonist drug MK 801 (dizocilpine). The time course of the progress of the lesions in untreated animals and the effect of neuropro- tection by MK 801 was continuously monitored In all test an- imals. Further, a relatively new inhalation anesthetic agent, isoflurane, has been employed. A more logical and semiquan- titative T2 bandwidth demarkation useful in distinguishing dif- ferent degrees of iesioning from the onset and up to the ‘edema’ stage through penumbra (mild lesion), medium de- gree lesion and severe lesion has been proposed. Key words: in vivo MRVMRS; brain lesions; drug treatment; tissue heterogeneity. INTRODUCTION The present work (1,2) using MRI and MRS techniques is an attempt to monitor the time course of brain lesions thait can be induced, for example, by the focal injection of excitatory aminoacids, and the follow-up of the progres- sion of the lesion due to neurodegeneration as well as assessment of curative effects of neuroprotective agents, all done with a view to examine the reliability of the NMR method and to evolve a procedure for the assess- ment of the state of the neurological disorders such as stroke, and the possible effect of drugs. Current medical hypothesis (3-6) associates certain neiirologic disorders such as stroke, trauma, after-effects of neurosurgery, Alzheimer’s and Parkinson’s disease, MRlM 30:174-182 zyxwvutsrqpon (1993) From the Boehringer lngelheim KG, the Department of Pharmacology (U.P.), the Department of ExperimentalPathology and Toxicology (L.H.), D-6507 In- geltieim, Germany (L.H.), the Fraunhofer Institute for Biomedical Engineer- ing, Magnetic Resonance Division, D-6670 St. Ingberl, Germany (H.K., W.K..), and the Indian Institute of Technology, Madras-600036, India (S.S.). Address correspondence to: Uwe Pschorn, M.D., Ph.D., Department of Pharmacology, Boehringer lngelheim KG, D-6507 Ingelheim/Rhein, Federal Republic of Germany. Received July 16, 1992; revised March 3, 1993; accepted March 25, 1993. Copyright zyxwvutsrqpo 0 1993 by Williams zyxwvutsrqpon 8 Wilkins All rights of reproduction in any form resewed. 0740-31 94/93 $3.00 etc., to neuroexcitotoxic properties of endogeneous or exogenous excitatory aminoacids interacting with the glutamate receptor complex (7). It has been known that such excitotoxic aminoacids which activate the glutamate receptor complex are involved in the patho- physiology of cerebral ischemia (8-12). The release of the excitotoxic aminoacids can also be triggered by oxygen and glucose starvation in the brain by an occluded blood vessel (13). In response to the glutamate, the NMDA re- ceptors open channels that allow passage of Na+ and Ca++ into the cells (14-17). Simultaneously the AMPA/ Kainate receptors also become activated and open addi- tional Na+ channels, resulting in an enormous build up of these ions inside the cells (6). It is also believed that excessive glutamate release can also activate the metabo- tropic receptors which trigger the formation of inositol 1,4,5-triphosphate and diacylglycerol leading to further release of Ca++ from intracellular calcium stores. Such enormous build up of Na+ triggers a transporter which exchanges Na+ for Ca++and the internal excess positive charge opens up voltage gated Ca++ channels. The ever increasing Ca+ leads to specific enzyme activated break up of DNA proteins and phopholipids zyx and the resulting metabolites block the previously healthy blood vessels spreading the ischemia (4). When unchecked, this leads to spread of the ‘lesion’ and to the death of the neurons. Drugs that would be effective in the control of stroke related neurodegeneration should attempt to block the above mentioned glutamate cascade (18-24). NMDA an- tagonists such as CGS 19755 (CIBA-GEIGY), MK 801 (Merck) and Dextrorphan (Hoffman-La Roche) are sup- posed to impede activation of NMDA receptors. Other drugs that can reduce the Ca++influx through the deac- tivation of voltage gated channels and dilate the blood vessels allowing the blood flow through the so-called ‘penumbra’ region (see later) may have additional ame- liorating effects when given along with the NMDA antag- onistic drugs (4). For the purpose of prototype research in such studies several approaches have been suggested in the literature as animal models. One can induce a typical focal cerebral infarction by direct stereotaxic injection in, say, the rat brain, of NMDA agonists or related receptor agonists (25) such as quinolinic acid, kainic acid, ibotenic acid, etc. as a model for excitotoxicity which is an excessive release of excitatory amino acids, following an initial event such as ischemia (stroke), after-effects of neurosurgery, etc. 174