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Neuroprotection by Δ9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, Against Ouabain-Induced in Vivo Excitotoxici

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Neuroprotection by Δ9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, Against Ouabain-Induced in Vivo Excitotoxici The Journal of Neuroscience, September 1, 2001, 21(17):6475–6479 Neuroprotection by ⌬9-Tetrahydrocannabinol, the Main Active Compound in Marijuana, against Ouabain-Induced In Vivo Excitotoxicity M. van der Stelt,1 W. B. Veldhuis,2,3 P. R. Ba¨r,3 G. A. Veldink,1 J. F. G. Vliegenthart,1 and K. Nicolay2 1Department of Bio-Organic Chemistry, Bijvoet Center for Biomolecular Research, 3584 CH, Utrecht University, Utrecht, The Netherlands, 2Department of Experimental In Vivo NMR, Image Sciences Institute, 3584 CJ, Utrecht, University Medical Center Utrecht, The Netherlands, and 3Department of Experimental Neurology, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands Excitotoxicity is a paradigm used to explain the biochemical SR141716 prevented the neuroprotective actions of ⌬9-THC, events in both acute neuronal damage and in slowly progres- indicating that ⌬9-THC afforded protection to neurons via the ⌬9 sive, neurodegenerative diseases. Here, we show in a longitu- CB1 receptor. In -THC-treated rats the volume of astrogliotic ⌬9 dinal magnetic resonance imaging study that -tetrahydro- tissue was 36% smaller. The CB1 receptor antagonist did not cannabinol (⌬9-THC), the main active compound in marijuana, block this effect. These results provide evidence that the can- reduces neuronal injury in neonatal rats injected intracerebrally nabinoid system can serve to protect the brain against with the Na ϩ/K ϩ-ATPase inhibitor ouabain to elicit excitotox- neurodegeneration. icity. In the acute phase ⌬9-THC reduced the volume of cyto- toxic edema by 22%. After 7 d, 36% less neuronal damage was Key words: anandamide; astrogliosis; cannabinoid; excitotox- observed in treated rats compared with control animals. Coad- icity; magnetic resonance imaging; neonatal rat; neuroprotec- ministration of the CB1 cannabinoid receptor antagonist tion; ouabain; THC The endogenous cannabinoid system comprises two cannabinoid accumulate when tissues and cells are subjected to excitotoxic receptors, designated CB1 and CB2, which have been cloned and stress (Hansen et al., 1998, 2000; Di Marzo et al., 2000; Sugiura et characterized (Di Marzo, 1998). Two main endogenous ligands al., 2000). Whether this increase in endocannabinoids is neuro- based on fatty acids, i.e., anandamide and 2-arachidonoylglycerol protective and if so via which mechanism is still under debate (2-AG) have been identified (Di Marzo, 1998). The CB1 receptor (Skaper et al., 1996a,b; Chan et al., 1998; Hampson et al., 1998; is mainly found in the CNS, whereas the CB2 receptor is almost Shen and Thayer, 1998; Andersson et al., 2000; Sinor et al., 2000). exclusively expressed by cells of the immune system (Pertwee, The therapeutic effects of cannabinoids in in vivo models of 1997). The discovery of the endogenous cannabinoid system cerebral ischemia are also not consistent. Chronic ⌬ 9-THC ad- initiated intense research into the therapeutic potential of canna- ministration has been shown to reduce the impact of an ischemic binoids in a variety of neurological and neurodegenerative disor- insult evoked by a reduced blood pressure and 12 min bilateral ders, such as gliomas, cerebral ischemia, and multiple sclerosis carotid artery occlusion. The involvement of the CB1 receptor (Nagayama et al., 1999; Baker et al., 2000; Galve-Roperh et al., was not studied (Louw et al., 2000). However, no protective effect 2000; Louw et al., 2000). could be found for WIN55.212-2, a synthetic CB-receptor ago- (Endo)cannabinoids have also been tested in models of excito- nist, in rats when the middle cerebral artery was occluded for 2 hr. toxicity, which is a concept of neuronal cell death caused by Surprisingly, the CB receptor antagonist SR141716 was protec- overactivation of excitatory amino acid receptors. The excitotox- 1 tive (C. J. Hillard, personal communication). Remarkably, WIN icity hypothesis is used to explain the common biochemical basis 55.212–2 afforded protection to hippocampal and cortical neurons behind many acute and chronic neurodegenerative disorders such in CB -dependent manner in rats with a permanent middle cere- as stroke, traumatic brain injury, amyotrophic lateral sclerosis, 1 Parkinson’s, Huntington’s, and Alzheimer’s diseases (Dirnagl et bral artery occlusion or global ischemia (Nagayama et al., 1999). al., 1999; Nicotera et al., 1999; Doble, 1999). N-acylethanol- The reason for this discrepancy is not known at the moment, but amines, including anandamide, and their precursors and 2-AG (endo)cannabinoid-induced vasorelaxation (Kunos et al., 2000) may have a different impact on the pathway of neuronal demise in each of these stroke models. Received March 22, 2001; revised May 31, 2001; accepted June 14, 2001. In light of the ambiguous results from both in vitro models of W.B.V. is financially supported by the Netherlands Organization for Scientific Research, Medical Sciences Council. We are indebted to H. Veldman and G. van excitotoxicity and in vivo models of cerebral ischemia, we inves- Haaften for expert technical assistance. Sanofi Recherche is gratefully acknowl- tigated the neuroprotective properties of ⌬ 9-THC in an in vivo edged for the gift of SR141716. We thank Dr. R. Dijkhuizen for fruitful discussions model of secondary excitotoxicity. Neurodegeneration was elic- and Dr. R. van Sluis for the development of the data analysis program. ϩ ϩ M.vdS. and W.B.V. contributed equally to the work. ited by inhibition of the Na /K -ATPase. Diffusion-weighted Correspondence should be addressed to G. A. Veldink, Department of Bio- magnetic resonance imaging (MRI), T2-weighted MRI, and his- organic Chemistry, Bijvoet Center for Biomolecular Research, Padualaan 8, 3584 9 CH, Utrecht University, Utrecht, The Netherlands. E-mail: [email protected]. tology, were used to study the effects of ⌬ -THC in both the acute Copyright © 2001 Society for Neuroscience 0270-6474/01/216475-05$15.00/0 and late phases after the induction of excitotoxicity. 6476 J. Neurosci., September 1, 2001, 21(17):6475–6479 van der Stelt et al. • Neuroprotection by ⌬9-THC MATERIALS AND METHODS Animal model. Neonatal Wistar rats (U:Wu/Cpb; 7- to 8-d-old) were anesthetized with ether and immobilized in a stereotaxic frame. A small burr hole was drilled in the cranium over the left hemisphere, 2.5 mm lateral of bregma. A 1 ␮l syringe was lowered into the left striatum to a depth of 4.0 mm (Dijkhuizen et al., 1996). Ouabain (0.5 ␮l1mM; n ϭ 30; Biomol, Zwijndrecht, The Netherlands) or vehicle (0.5 ␮l40mM Tris- HCl buffer, pH 7.4; n ϭ 2) was injected at a rate of 0.125 ␮l/min with a microdrive. After injection the needle was left in situ for 2 min to avoid leakage of injection fluid from the needle tract. Animals were then positioned in the magnet, and anesthesia was continued with a mixture of halothane (0.4–1%) in N2O/O2. Body temperature was maintained at 37°C using a water-filled heating pad and an infrared heating lamp. Animals were treated with ⌬ 9-THC (Sigma Aldrich; n ϭ 12), THC ϩ SR141716 (n ϭ 5; Sanofi Recherche, Montpellier, France), SR141716 (n ϭ 6) (all drugs at 1 mg/kg in 1 ml/kg body weight 18:1:1 v/v PBS/Tween 80/Ethanol) 30 min before toxin injection. There was no difference in body weight and growth rate between any of the groups. The vehicle intraperitoneal injection did not affect lesion size. The University’s Animal Experimental Committee approved all protocols. MRI experiments. MRI was performed on a 4.7 T Varian horizontal bore spectrometer. Excitation and signal detection were accomplished by means of a Helmholtz volume coil (9 cm) and an inductively coupled surface coil (2 cm), respectively. A single-scan diffusion-trace MRI se- quence [four b values:100–1300 sec/mm 2; repetition time (TR), 3 sec; echo time (TE), 100 msec] was used to generate quantified images of tissue water trace apparent diffusion coefficient (ADC). Diffusion trace- and T2-weighted-imaging (TE, 18, 40, 62, and 84 msec; TR, 2 sec; number of transients, 2) were performed in all animals, starting at t ϭ 15 min after injection on day 0 and were repeated 1 week later. Figure 1. Three adjacent coronal ADC maps of neonatal rat brain 15 min after ouabain injection. a, No treatment; b, THC treatment; c, THC Both the T 2-weighted and the diffusion-weighted datasets consisted of ϩ seven consecutive, 1.5-mm-thick slices, with 0 mm slice gap. To minimize SR141716 treatment. Hypointensities correlate to cytotoxic edema. interference at the slice boundaries, slices were acquired in alternating order (1, 3, 5, 7, 2, 4, 6), thus maximizing the time between excitation of RESULTS two neighboring slices. For the diffusion-weighted imaging we used a double spin-echo pulse sequence with four pairs of bipolar gradients with Loss of cellular ion homeostasis was initiated by unilateral intra- ϩ ϩ specific predetermined signs in each of the three orthogonal directions as striatal injection of 0.5 ␮l of the Na /K -ATPase inhibitor recently published by De Graaf et al. (2001). The combination of gradi- ouabain (1 mM) into 7- to 8-d-old Wistar rats (Lees et al., 1990; ent directions leads to cancellation of all off-diagonal tensor elements, effectively measuring the trace of the diffusion tensor. This provides Lees, 1991; Lees and Leong, 1995; Stelmashook et al., 1999). 9 unambiguous and rotationally invariant ADC values in one experiment, Twelve animals received an additional injection with ⌬ -THC (1 ⌬ 9 circumventing the need for three separate experiments. For each b value, mg/kg, i.p.), and five animals received both -THC and the CB1 two scans were averaged. The total scan time for acquisition of seven antagonist SR141716 (1 mg/kg, i.p.) 30 min before ouabain slices, with four b values and two averages, was 17 min.
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