Three-dimensional MRI of cerebral projections in rat brain in vivo after intracortical injection of MnCl2

In this study we investigated the potential of in vivo MRI detection of axonal Mn2+ transport for tracing neuronal projections originating in the sensorimotor cortex in healthy and lesioned rat brains. Special attention was given to the potential of visualizing neuronal sprouting of central nervous system across the midline. After injecting unchelated MnCl2 into the forelimb area of sensorimotor cortex of 18 healthy and 10 lesioned rats corticofugal projections could be traced through the internal capsule to the cerebral peduncle and the pyramidal decussation. Although the neuronal tract was visible as early as 6 h after MnCl2 injection, best contrast was achieved after 24-48 h. Beside the cortico-spinal tract, the cortico-thalamic fibres were also visualized by anterograde Mn2+ transport. Cortico-striatal fibres were partially masked by the very high signal near the MnCl2 injection site but could be discerned as well. Slight, diffuse signal enhancement of cortical tissue contralateral to the MnCl2 injection site in healthy rat brains suggests interhemispheric connections or passive diffusion of Mn2+. However, enhanced fibre tract contrast connecting both hemispheres was visible 16 weeks after onset of focal photothrombotic cortical injury. In conclusion our study has shown that we were able to visualize reproducibly the main descending corticofugal projections and interhemispheric connections by non-invasive MRI after localized injection of MnCl2. The appearance of interhemispheric Mn2+-enhanced fibres after photothrombotic focal injury indicates that the method may bear potential to follow non-invasively gross plastic changes of connectivity in the brain after injury.     

Manganese enhancement in non-CNS organs

Manganese-enhanced magnetic resonance imaging (MEMRI) is a novel imaging technique capable of monitoring calcium influx, in vivo. Manganese (Mn2+) ions, similar to calcium ions (Ca2+), are taken up by activated cells where their paramagnetic properties afford signal enhancement in T(1)-weighted MRI methodologies. In this study we have assessed Mn2+ distribution in mice using magnetization-prepared rapid gradient echo (MP-RAGE) based MRI, by measuring changes in T(1)-effective relaxation times (T(1)-eff), effective R(1)-relaxation rates (R(1)-eff) and signal intensity (SI) profiles over time. The manganese concentration in the tissue was also determined using inductively coupled plasma atomic emission spectrometry (ICP-AES). Our results show a strong positive correlation between infused dose of MnCl2 and the tissue manganese concentration. Furthermore, we demonstrate a linear relationship between R(1)-eff and tissue manganese concentration and tissue-specific Mn2+ distribution in murine tissues following dose-dependent Mn2+ administration. This data provides an optimized MnCl2 dose regimen for an MP-RAGE based sequence protocol for specific target organs and presents a potential 3D MRI technique for in vivo imaging of Ca2+ entry during Ca2+-dependent processes in a wide range of tissues.     

Manganese-enhanced magnetic resonance imaging (MEMRI) without compromise of the blood-brain barrier detects hypothalamic neuronal activity in vivo

There is growing interest in the use of manganese-enhanced MRI (MEMRI) to detect neuronal activity and architecture in animal models. The MEMRI neuronal activity studies have been generally performed either by stereotactic brain injection or by systemic administration of Mn(2+) in conjunction with the disruption of the blood-brain barrier (BBB). These approaches, however, have limited the use of MEMRI because of the procedure-related morbidity/mortality or because brain activity measured by these methods can diverge from genuine physiological responses. In this study, the hypothesis that MEMRI, performed with systemic administration of Mn(2+) without compromising the BBB integrity, is able to detect hypothalamic function associated with feeding was tested. This procedure was tested on a simple physiological condition, fasting, and with this method temporal and regional differences in Mn(2+) enhancement could be detected. It is concluded that MEMRI can be used to study hypothalamic function in the murine brain without compromising the BBB. It was also shown that region-specific Mn(2+) enhancement in the mouse brain can be modulated by fasting. More importantly, this non-invasive in vivo imaging technique is able to demonstrate differences in brain activities, previously possible only by in vitro studies.     

The entry of manganese ions into the brain is accelerated by the activation of N-methyl-D-aspartate receptors

Manganese-enhanced magnetic resonance imaging (MEMRI) is receiving increased interest as a valuable tool for monitoring the physiological functions in the animal brain based on the ability of manganese ions to mimic calcium ions entering to excitable cells. Here the possibility that in vivo MEMRI can detect the entry of manganese ions (Mn2+) in the brain of rats behaving without intended stimulation is tested. This hypothesis was a result of the unexpected observation that Mn2+-dependent signal enhancement was dramatically suppressed in ketamine-anesthetized rats compared with other anesthetics, such as urethane, pentobarbital and isoflurane. The effects of noncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonists, ketamine and MK-801, on MEMRI for MnCl2 injected rats were examined. Treatment with MK-801 suppressed the signal enhancement more effectively than with ketamine. NMDAR agonists, glutamate (100 mg/kg) and N-methyl-d-aspartate (NMDA) (35 mg/kg), enhanced the signal intensities on MEMRI, and this signal enhancement was completely antagonized by MK-801. The systemic administration of the competitive NMDAR antagonist, D-2-amino-5-phosphono-pentanoate (D-AP5), which does not cross the blood-brain barrier (BBB), showed no effects on the signal enhancement induced by NMDA and glutamate. A selective AMPA receptor (AMPAR) antagonist, 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX), did not block the signal enhancement. These data indicated that the Mn2+-dependent signal enhancement took place as a result of the activation of glutamatergic neurons through NMDAR, but not through AMPAR in the brain.     

Monitoring dynamic alterations in calcium homeostasis by T (1)-weighted and T (1)-mapping cardiac manganese-enhanced MRI in a murine myocardial infarction model

Manganese has been used as a T(1)-weighted MRI contrast agent in a variety of applications. Because manganese ions (Mn(2+)) enter viable myocardial cells via voltage-gated Ca(2+) channels, manganese-enhanced MRI is sensitive to the viability and inotropic state of the heart. In spite of the established importance of Ca(2+) regulation in the heart both before and after myocardial injury, monitoring strategies to assess Ca(2+) homeostasis in affected cardiac tissues are limited. This study implements a T(1)-mapping method to obtain quantitative information both dynamically and over a range of MnCl(2) infusion doses. To optimize the current Mn(2+) infusion protocols, we performed both dose-dependent and temporal washout studies. A non-linear relationship between infused MnCl(2) solution dose and increase in left ventricular wall relaxation rate (DeltaR(1)) was observed. Control mice also exhibited significant Mn(2+) clearance over time, with a decrease in DeltaR(1) of approximately 50% occurring in just 2.5 h. The complicated efflux time dependence possibly suggests multiple efflux mechanisms. With the use of the measured relationship between infused Mn(2+) dose, DeltaR(1), and inductively coupled plasma mass spectrometry data analysis provided a means of estimating the absolute heart Mn concentration in vivo. We show that this technique has the sensitivity to observe or monitor potential alterations in Ca(2+) handling in vivo because of the physiological remodeling after myocardial infarction. Left ventricular free wall DeltaR(1) values were significantly lower (P = 0.005) in the adjacent zone, surrounding the injured myocardial tissue, than in healthy tissue. This inferred reduction in Mn concentration can be used to estimate potentially salvageable myocardium in vivo for future treatment or evaluation of disease progression.     

Applications of manganese-enhanced magnetic resonance imaging (MEMRI) to imaging of the heart

The use of manganese-based MRI contrast materials, either manganese salts or chelates, has spanned the entire timeframe of cardiac MRI. However interest in Mn compounds for cardiac MRI has been sporadic because of concerns over cardiotoxicity associated with significant concentration of free Mn2+ and notable success of gadolinium chelates in cardiac application. Initial strategies to overcome cardiotoxicity included chelation of Mn2+ to reduce the concentration of the free ion in vivo, and addition of Ca2+ in combination with Mn2+ to competitively reduce binding of Mn2+ to Ca2+ channels in the heart. Both approaches met with mixed success, but were subsequently discontinued in favor of gadolinium-based approaches. However Mn2+-based media potentially offer unique advantages for characterizing heart pathology over conventional Gd-based contrast media because Mn2+ is taken up by heart cells and retained for hours. Cellular uptake occurs through calcium channels so contrast on delayed images may be interpreted according to regional or global functional status. Since Mn2+ is retained in the heart, Mn-based media can be administered outside the magnet and the contrast pattern measured hours later to provide assessment of uptake. A key issue is whether sufficient accumulation of Mn2+ in heart cells for imaging can occur without cardiotoxicity, and findings to date indicate this is possible. This review examines the current status of Mn2+-enhanced MRI of heart with particular focus on the hypothesis that Mn2+ uptake can be interpreted in terms of heart function.     

Manganese-enhanced magnetic resonance imaging (MEMRI): methodological and practical considerations

Manganese-enhanced MRI (MEMRI) is being increasingly used for MRI in animals due to the unique T1 contrast that is sensitive to a number of biological processes. Three specific uses of MEMRI have been demonstrated: to visualize activity in the brain and the heart; to trace neuronal specific connections in the brain; and to enhance the brain cytoarchitecture after a systemic dose. Based on an ever-growing number of applications, MEMRI is proving useful as a new molecular imaging method to visualize functional neural circuits and anatomy as well as function in the brain in vivo. Paramount to the successful application of MEMRI is the ability to deliver Mn2+ to the site of interest at an appropriate dose and in a time-efficient manner. A major drawback to the use of Mn2+ as a contrast agent is its cellular toxicity. Therefore, it is critical to use as low a dose as possible. In the present work the different approaches to MEMRI are reviewed from a practical standpoint. Emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn2+ to the target areas of interest.     

IR-SE and IR-MEMRI allow in vivo visualization of oscine neuroarchitecture including the main forebrain regions of the song control system

Songbirds share with humans the capacity to produce learned vocalizations (song). Recently, two major regions within the songbird's neural substrate for song learning and production; nucleus robustus arcopallii (RA) and area X (X) are visualized in vivo using Manganese Enhanced MRI (MEMRI). The aim of this study is to extend this to all main interconnected forebrain Song Control Nuclei. The ipsilateral feedback circuits allow Mn2+ to reach all main Song Control Nuclei after stereotaxic injection of very small doses of MnCl2 (10 nl of 10 mM) into HVC of one and MAN (nucleus magnocellularis nidopallii anterioris) of the other hemisphere. Application of a high resolution (80 micron) Spin Echo Inversion Recovery sequence instead of conventional T1-weighted Spin Echo images improves the image contrast dramatically such that some Song Control Nuclei, ventricles, several laminae, fibre tracts and other specific brain regions can be discerned. The combination of this contrast-rich IR-SE sequence with the transsynaptic transport property of Manganese (Inversion Recovery based MEMRI (IR-MEMRI)) enables the visualization of all main interconnected components of the Song Control System in telencephalon and thalamus.     

Neuroimaging of cortical development and brain connectivity in human newborns and animal models

Significant human brain growth occurs during the third trimester, with a doubling of whole brain volume and a fourfold increase of cortical gray matter volume. This is also the time period during which cortical folding and gyrification take place. Conditions such as intrauterine growth restriction, prematurity and cerebral white matter injury have been shown to affect brain growth including specific structures such as the hippocampus, with subsequent potentially permanent functional consequences. The use of 3D magnetic resonance imaging (MRI) and dedicated postprocessing tools to measure brain tissue volumes (cerebral cortical gray matter, white matter), surface and sulcation index can elucidate phenotypes associated with early behavior development. The use of diffusion tensor imaging can further help in assessing microstructural changes within the cerebral white matter and the establishment of brain connectivity. Finally, the use of functional MRI and resting-state functional MRI connectivity allows exploration of the impact of adverse conditions on functional brain connectivity in vivo. Results from studies using these methods have for the first time illustrated the structural impact of antenatal conditions and neonatal intensive care on the functional brain deficits observed after premature birth. In order to study the pathophysiology of these adverse conditions, MRI has also been used in conjunction with histology in animal models of injury in the immature brain. Understanding the histological substrate of brain injury seen on MRI provides new insights into the immature brain, mechanisms of injury and their imaging phenotype.     

磁共振DTI技术和锰离子示踪方法活体定位鼠脑神经纤维

本文应用磁共振(MR)DTI的方法清晰准确描绘出鼠脑白质内主要神经纤维的位置、方向和形态,包括胼胝体、前联合、内囊、外囊、视束、大脑脚、锥体束等。皮质内注射MnCl2后MR成像,可见皮质脊髓束、皮质丘脑束、皮质纹状体束和纹状体黑质通路被示踪,可重复性地表现为特定部位的MR3D-FSPGR图像和T1W像高信号改变,相应区域T2WI为低信号。LFB染色各纤维束位置、形态与DTI-DEC张量图和MnCl2示踪MR图像结果相一致。因此,磁共振DTI技术和锰离子示踪的方法都能够对鼠脑主要神经纤维和投射通路进行定位,能够作为活体示踪脑内神经纤维束的手段。     

Manganese-enhanced magnetic resonance imaging (MEMRI) of brain activity and applications to early detection of brain ischemia

Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced.     

The immune dysregulatory compound mercuric chloride induces integrin-mediated T-lymphocyte adhesion

Exposure of Brown Norway rats to mercuric chloride induces systemic autoimmunity, involving T- and B-lymphocyte activation, (auto-)antibody production and multiorgan inflammation. Several divalent metal ions, such as Mg2+ and Mn2+, can activate binding of integrins to their ligands, thus causing lymphocyte adhesion. To test the hypothesis that Hg2+ acts in a similar way, we studied the effect of HgCl2 on integrin-mediated T-cell adhesion. HgCl2 induced cell-cell aggregation of human T lymphoblasts. Exposure of a human T-cell clone to HgCl2 for 1 hr enhanced, in a dose-dependent way, cell binding to fibronectin (FN) and to intercellular adhesion molecules (ICAM) -1, -2 and -3. Furthermore, HgCl2 induced strong binding of Jurkat T cells to FN. These effects of HgCl2 were of similar magnitude as the effects of phorbol 12-myristate 13-acetate (PMA) or MnCl2. Studies using blocking antibodies indicated the involvement of CD11a in binding to ICAMs, and of CD49d, CD49e, and CD29 in binding to FN. Adhesion to FN induced by HgCl2 or by PMA, but not by MnCl2, was dependent on temperature and on extracellular Ca2+ or Mg2+. Addition of cytochalasin B enhanced synergistically the FN adhesion induced by MnCl2, whereas the effects of PMA and HgCl2 were not modified. These results indicate that Hg2+ is a potent activator of T-cell adhesion, mediated by several integrins and ligands. In contrast to the effect of MnCl2, HgCl2-induced cell adhesion probably involves an intracellular pathway. Activation of integrins by HgCl2 may play an important role in activation and migration of leucocytes involved in HgCl2-induced immune dysregulation in vivo.     

Effect of paramagnetic manganese cations on (1)H MRS of the brain

Manganese cations (Mn(2+)) can be used as an intracellular contrast agent for structural, functional and neural pathway imaging applications. However, at high concentrations, Mn(2+) is neurotoxic and may influence the concentration of (1)H MR-detectable metabolites. Furthermore, the paramagnetic Mn(2+) cations may also influence the relaxation of the metabolites under investigation. Consequently, the purpose of this study was to investigate the effect of paramagnetic Mn(2+) cations on (1)H-MR spectra of the brain using in vivo and phantom models at 4.7 T. To investigate the direct paramagnetic effects of Mn(2+) cations on the relaxation of N-acetylaspartate (NAA), creatine and choline, T(1) relaxation times of metabolite solutions, with and without 5% albumin, and containing different Mn(2+) concentrations were determined. Relaxivity values with/without 5% albumin for NAA (4.8/28.1 s(-1) mM(-1)), creatine (2.8/2.8 s(-1) mM(-1)) and choline (1.8/1.1 s(-1) mM(-1)) showed NAA to be the most sensitive metabolite to the relaxation effects of the cations. Using an in vivo optic tract tracing imaging model, we obtained two adjacent regions of interest in the superior colliculi with different water T(1) values (Mn(2+)-enhanced = 1.01 s; unenhanced = 1.14 s) 24 h after intravitreal injection of 3 microL 50 mM MnCl(2). Using phantom and in vivo water relaxation time data, we estimated the in vivo Mn(2+) concentration to be 2-8 microM. The phantom data suggest that limited metabolite relaxation effects would be expected at this concentration. Consequently, this study indicates that, in this model, the presence of Mn(2+) cations does not significantly affect (1)H-MR spectra despite possible toxic and paramagnetic effects.     

Manganese-enhanced MRI of acute cardiac ischemia and chronic infarction in pig hearts: kinetic analysis of enhancement development

To assess infarction development in pig hearts, Mn-enhanced and Gd-enhanced MRI were used. In domestic pigs (25-35 kg, n = 37), the first and second diagonal branches of the left anterior descending coronary artery were ligated to induce acute ischemia and infarction (ischemia+reperfusion) or chronic infarction of increasing duration (3- 28 days). Ex vivo experiments were performed on hearts perfused in the Langendorff mode with a 50:50 mixture of blood and Krebs-Henseleit buffer using a spin-echo sequence on a 7 T Bruker imaging system. Signal acquisition from the heart and two reference test tubes (H(2)O and H(2)O + 10 mM CuSO(4)) was gated by the left ventricular pressure wave. T(1)-weighted images of six 8 mm short-axis slices (2 mm interslice gaps) were obtained before and after the addition of 0.2 mM MnCl(2) every 5 min over a 30-45 min period. Signal intensities were normalized to those of the H(2)O reference and fitted by a monoexponential function. The rates of intensity increase and maximal increases were significantly lower in the ischemic/infarcted areas and showed a trend to rise on infarction progression. In vivo Gd-enhanced MRI (3 T Siemens scanner) and in vivo/ex vivo near-infrared imaging confirmed major Mn-enhanced MRI findings. Triphenyltetrazolium chloride staining revealed necrotic areas in all chronic infarctions and no necrosis after acute ischemia. We conclude that MnCl(2) highlights ischemic areas because of the low collateral flow characteristic of pig hearts, whereas in the infarcted areas with substantial perfusion, scar tissue components are important for contrast distribution.     

Medial temporal lobe abnormalities in pediatric unipolar depression

In vivo anatomical magnetic resonance imaging (MRI) studies in adults with major depressive disorder (MDD) have implicated neurocircuitries involved in mood regulation in the pathophysiology of mood disorders. Specifically, abnormalities in the medial temporal lobe structures have been reported. This study examined a sample of children and adolescents with major depressive disorder to investigate anatomical abnormalities in these key medial temporal brain regions. Nineteen children and adolescents with DSM-IV major depression (mean age +/- S.D.=13.0 +/- 2.4 years; 10 unmedicated) and 24 healthy comparison subjects (mean age +/- S.D.=13.9 +/- 2.9 years) were studied using a 1.5T Philips MRI scanner. We measured hippocampus and amygdala gray matter volumes. MRI structural volumes were compared using analysis of covariance with age and total brain volumes as covariates. Pediatric depressed patients had significantly smaller left hippocampal gray matter volumes compared to healthy controls (1.89 +/- 0.16 cm(3) versus 1.99 +/- 0.18 cm(3), respectively; F=5.0, d.f.=1/39, p=0.03; effect size: eta2(p) =0.11). Unmedicated depressed patients showed a trend towards smaller left hippocampal volumes compared to medicated patients and healthy subjects (F=2.8, d.f.=2/38, p=0.07; effect size: eta2(p) =0.13). There were no statistically significant differences in mean volumes for left or right amygdala. Smaller left hippocampal volumes in children and adolescents with MDD are in agreement with findings from adult studies and suggest that such abnormalities are present early in the course of the illness. Amygdala volumes are not abnormal in this age group. Smaller hippocampal volumes may be related to an abnormal developmental process or HPA axis dysfunction.     

Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride

There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra-small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T1-weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05-1.0 mM MnCl2. A flow cytometry-based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24 h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their in vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI-based cell migration studies.     

Effects of divalent cations and of catecholamines on the late response of the superior cervical ganglion.

The characteristics of the late response of the superior cervical ganglion of dogs were studied by close-arterial injection of catecholamines and divalent cations to the ganglion. 2. Dopamine, noradrenaline and adrenaline inhibit the late response as well as ganglionic activity induced by other means. The effect of dopamine is brief but that of adrenaline is prolonged. 3. Cd2+, Co2+, Ni2+, Zn2+, Hg2+ and Fe2+ markedly potentiate the late response, whereas Mn2+, Ca2+ and Mg2+ inhibit it. 4. may potentiate ganglionic activity triggered by other ganglionic stimulants. The Cd-augmented activity may be blocked by a ganglion-blocker which is specific to the stimulant. 5. CdCl2 may exhibit a direct ganglion-stimulating action on a ganglion which shows prominent late responses and has been conditioned by tetanic preganglionic stimulation. 6. CdCl2 and MnCl2 may inhibit ganglionic transmission by suppressing acetylcholine release from presynaptic nerve terminals. 7. It is concluded that the late response represents the late discharges of ganglion cells, which are very sensitive to inhibition by CaCl2 and MnCl2 and may be potentiated by CdCl2.     

β淀粉样蛋白25～35急性给药和慢性孵育对神经元Ca2+非依赖性的K+电流作用的比较

目的 探讨β-淀粉样蛋白25～35（Aβ _25-35）急性给药和慢性孵育对神经元Ca ²⁺非依赖性的K+电流作用的区别。 方法 急性分离大鼠海马及培养皮层神经元; Aβ25-35急性给药(3min)或慢性孵育（24h）;利用全细胞膜片钳技术记录Ca2+非依赖性的K+电流以及Calcein-AM法检测神经元活力。 结果 Aβ _25-35急性给药使急性分离的海马神经元Ca ²⁺非依赖性的K+电流幅度明显降低(n=11),而慢性孵育则使培养的皮层神经元该电流幅度明显升高(n=11)。前者是Aβ _25-35通过对K+通道直接的效应发挥其抑制作用,而后者可能主要是通过Aβ _25-35上调通道蛋白,改变通道数量而发挥作用。 结论 不同的给药方式通过不同的机制对海马和皮层神经元的Ca ²⁺非依赖性的K+电流产生不同的作用。     

Regional cerebral pharmacokinetics of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as examined by positron emission tomography in a baboon is altered by tranylcypromine

The selective dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has chemical and metabolic characteristics which allow its in vivo tissue distribution to be studied using positron emission tomography (PET). The cerebral pharmacokinetics of [¹¹C]MPTP labelled at the N-methyl position was quantitatively traced in the living brain of an anesthetized baboon using PET, and the effect of administration of the monoamine oxidase (MAO) inhibitor tranylcypromine on this regional cerebral distribution was determined in the same animal. Following injection of [¹¹C]MPTP, radioactivity rapidly concentrated in the basal ganglia of the primate's brain. This in vivo localization was prevented by prior administration of tranylcypromine, suggesting that it is oxidized metabolites of MPTP which are sequestered by dopaminergic neurons. Radioactivity rapidly localized preferentially in the basal ganglia of the primate brain, and this in vivo localization was blocked by prior administration of the MAO inhibitor tranylcypromine.     

Are cannabinoid drugs neurotoxic or neuroprotective?

Chronic exposure to cannabinoids was shown to induce long lasting impairment of learning and memory, which was accompanied by morphological damage to the brain. On the other hand, several studies have shown that cannabinoids can protect from various brain traumas. This enigmatic dualism is explained herein by a comprehensive hypothesis, which is based on our recent in vitro studies and on pharmacokinetic in vivo considerations. The hypothesis predicts that low concentrations of cannabinoids will be neurotoxic while high concentrations of the drugs will protect from neuronal damage, and suggests that chronic administration of cannabinoids will induce neuronal death, while their acute administration will protect the brain. We further propose straight forward experiments, both in vivo (animal models for brain damage) and in vitro (cell death in neuronal cultures) to verify this hypothesis. The outcome of these experiments may have practical applications when considering the use of cannabinoids as therapeutic agents and in evaluating the consequences of their use as recreational drugs.