title: Assessment of 2-chloroadenosine treatment after experimental traumatic brain injury in the rat using arterial spin-labeled MRI: a preliminary report.
abstract: Adenosine is a putative endogenous neuroprotectant. Its action at A1 receptors mitigates excitotoxicity while action at A2 receptors increases cerebral blood flow (CBF). We hypothesized that cerebral injection of the adenosine analog, 2-chloroadenosine, would decrease swelling and increase CBF early after experimental traumatic brain injury (TBI). To test this hypothesis, rats were anesthetized and subjected to TBI using a controlled cortical impact (CCI) model (n = 5/group). Immediately after injury, 2-chloroadenosine (0.3 nmole in 2 microliters) or an equal volume of vehicle were stereotactically injected lateral to the area of contusion. Using magnetic resonance imaging (MRI), in vivo spin-lattice relaxation time of tissue water (Tlobs) and CBF (arterial spin labeling) were measured in a 2-mm thick slice in the injured and non-injured hemispheres at 3-4 h after CCI. In a separate, preliminary experiment, the effect of 2-chloroadenosine injection in normal rat brain was studied. Rats (n = 2) were anesthetized and a burr hole was made for injection of 2-chloroadenosine into the same site as in the TBI model. One rat received the standard dose of 0.3 nmole and one rat received a 6 nmole injection. Tlobs and CBF studies were obtained 1.5-3.5 h after injection, using the same MRI methods as in the TBI study. In rats subjected to TBI, treatment with 2-chloroadenosine attenuated the increase in Tlobs after injury (p < 0.05 for treatment vs vehicle) in both hippocampus and cortex ipsilateral to injury. However, treatment with 2-chloroadenosine did not improve post-traumatic hypoperfusion. In normal rats, injection of 0.3 nmole of 2-chloroadenosine did not increase CBF, but the higher dosage of 6 nmole dramatically increased hemispheric CBF by 1.5-2.0-fold. The effect of local injection of 2-chloroadenosine at a dose of 0.3 nmole after experimental TBI on Tlobs presumably represents a reduction in post-traumatic edema. This reduction in edema, along with the augmentation of CBF seen in normal rats at higher dosage (6 nmole), supports a role for adenosine in neuroprotection following TBI.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Pittsburgh, Pennsylvania, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Robertson
authors.forename: K S
authors.initials: KS
authors.lastname: Hendrich
authors.forename: P M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: E K
authors.initials: EK
authors.lastname: Jackson
authors.forename: J A
authors.initials: JA
authors.lastname: Melick
authors.forename: S H
authors.initials: SH
authors.lastname: Graham
authors.forename: D W
authors.initials: DW
authors.lastname: Marion
authors.forename: D S
authors.initials: DS
authors.lastname: Williams
authors.forename: C
authors.initials: C
authors.lastname: Ho
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology*; D000241:Adenosine / Q000502:physiology; D000818:Animals; D001924:Brain Concussion / Q000473:pathology / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000098:blood supply / Q000293:injuries* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D007089:Image Enhancement; D007267:Injections; D008279:Magnetic Resonance Imaging; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
chemical_list: D015762:2-Chloroadenosine; D000241:Adenosine