dizocilpine-maleate and Craniocerebral-Trauma

Endogenous cannabinoid receptor ligands (endocannabinoids) may rescue neurons from glutamate excitotoxicity. As these substances also accumulate in cultured immature neurons following neuronal damage, elevated endocannabinoid concentrations may be interpreted as a putative neuroprotective response. However, it is not known how glutamatergic insults affect in vivo endocannabinoid homeostasis, i.e. N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), as well as other constituents of their lipid families, N-acylethanolamines (NAEs) and 2-monoacylglycerols (2-MAGs), respectively. Here we employed three in vivo neonatal rat models characterized by widespread neurodegeneration as a consequence of altered glutamatergic neurotransmission and assessed changes in endocannabinoid homeostasis. A 46-fold increase of cortical NAE concentrations (anandamide, 13-fold) was noted 24 h after intracerebral NMDA injection, while less severe insults triggered by mild concussive head trauma or NMDA receptor blockade produced a less pronounced NAE accumulation. By contrast, levels of 2-AG and other 2-MAGs were virtually unaffected by the insults employed, rendering it likely that key enzymes in biosynthetic pathways of the two different endocannabinoid structures are not equally associated to intracellular events that cause neuronal damage in vivo. Analysis of cannabinoid CB(1) receptor mRNA expression and binding capacity revealed that cortical subfields exhibited an up-regulation of these parameters following mild concussive head trauma and exposure to NMDA receptor blockade. This may suggest that mild to moderate brain injury may trigger elevated endocannabinoid activity via concomitant increase of anandamide levels, but not 2-AG, and CB(1) receptor density.

Topics: Animals; Arachidonic Acids; Brain Concussion; Cannabinoid Receptor Modulators; Cerebral Cortex; Corpus Striatum; Craniocerebral Trauma; Dizocilpine Maleate; Endocannabinoids; Ethanolamines; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycerides; Male; N-Methylaspartate; Nerve Degeneration; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley; Receptors, Cannabinoid; Receptors, Drug; RNA, Messenger

We previously described the time course of changes in neurologic status (as indicated by neurologic severity score [NSS]) and cerebral edema (as indicated by brain tissue specific gravity and water content) after closed head trauma in rats. The present study was designed to determine whether head trauma alters the integrity of the blood-brain barrier (BBB), the role of the BBB in edema formation and neurologic outcome, and the effect of MK-801 (a noncompetitive N-methyl-D-aspartate receptor antagonist) on BBB permeability. Rats in which cranial impact was delivered during ether anesthesia (n = 106) were killed at 15 min, 1, 2, 4, 10, and 24 h, and 2, 4, and 7 days. Control rats (n = 12) received no cranial impact. Subsets of head-injured rats killed at 4 and 24 h received MK-801 (3 mg/kg intraperitoneally) 1 h after injury. BBB permeability was assessed with intravenous injection of Evans Blue dye, cerebral edema was assessed by determining brain tissue specific gravity and water content, and neurologic status was assessed using NSS. Tissue extravasation of Evans Blue was maximal in the injured hemisphere 4 h after injury, but a residual BBB permeability defect was still evident as long as 4 days after the insult. In MK-801-treated rats, extravasation of Evans Blue in the injured hemisphere was not significantly different from that in the noninjured hemisphere.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Blood-Brain Barrier; Brain Edema; Cell Membrane Permeability; Craniocerebral Trauma; Dizocilpine Maleate; Evans Blue; Extravasation of Diagnostic and Therapeutic Materials; Injury Severity Score; Male; Models, Neurological; Rats; Specific Gravity