Intracerebral injection of AMPA causes axonal damage in vivo.

Brain injury following acute and chronic neurological conditions can involve both neuronal perikaryal and axonal damage, yet considerably less is known about the mechanisms of axonal damage. Oligodendrocytes and myelin are highly vulnerable to AMPA receptor-mediated excitotoxicity. In vitro studies using isolated white matter preparations have shown that AMPA receptor-mediated excitotoxicity results in axonal damage. The effect of AMPA on axons in vivo remains to be determined. We established an in vivo model to determine if axons were vulnerable to AMPA-mediated toxicity, and furthermore, to examine if axonal damage occurred through an AMPA receptor-mediated mechanism. Adult rats received stereotaxic injection of AMPA (2.5 or 25 nmol) or vehicle (PBS) into the external capsule. Axonal damage was detected in the external capsule and cortex in sections immunostained for cytoskeletal components microtubule associated protein-5 (MAP 5), the 200 kDa neurofilament subunit (NF 200) and non-phosphorylated neurofilament-H (SMI 32). Quantification of axonal damage in the external capsule of MAP 5-immunostained sections showed that AMPA caused a significant, dose-dependent increase in axonal damage compared to the vehicle-treated controls. AMPA also induced a dose-dependent increase in myelin and neuronal perikaryal damage. Systemic administration of the AMPA receptor antagonist SPD 502 significantly reduced the amount of AMPA-induced axonal, myelin and neuronal damage. These data suggest that AMPA induces structural damage to the cytoskeleton of axons in vivo, as well as neuronal and myelin damage, and that this occurs through AMPA receptor-mediated mechanisms. AMPA receptor antagonism may have therapeutic potential to salvage both axons and neuronal perikarya in a number of neurological disorders.

Sipatrigine and oligodendrocyte and axonal pathology following transient focal cerebral ischaemia in the rat.

The ability of Sipatrigine (BW619c89), a sodium and calcium channel blocker to protect neuronal perikarya, axons and oligodendrocytes from ischaemia has been evaluated in the rat. Sipatrigine (30 mg/kg) was administered 15 min prior to transient (2 h) occlusion of the middle cerebral artery with animals being sacrificed 24 h after induction of ischaemia. Sipatrigine significantly reduced the volumes of neuronal perikarya damage (by 35%) and oligodendrocyte damage (by 54%). Sipatrigine minimally altered axonal damage (median scores: vehicle approximately 30, Sipatrigine approximately 26). The present report provides evidence that neuronal perikarya, axons and oligodendrocytes may be differentially protected by pharmacological intervention in focal cerebral ischaemia.

Grey matter and white matter ischemic damage is reduced by the competitive AMPA receptor antagonist, SPD 502.

Protection of both grey and white matter is important for improvement in stroke outcome. In the present study the ability of a competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist to protect axons, oligodendrocytes, and neuronal perikarya, was examined in a rodent model of transient focal cerebral ischemia. SPD 502 (8-methyl-5-(4-( -dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-o(4-hydroxybutyricacid-2-yl)oxime) was administered as an intravenous bolus (16 mg/kg) 15 minutes before transient (3-hour) middle cerebral artery (MCA) occlusion, followed by an intravenous infusion (16 mg kg(-1) hr(-1)) of the drug for 4 hours. Twenty-one hours after ischemia, axonal damage was reduced by 45% (P = 0.006) in the SPD 502-treated group compared with the vehicle. The anatomic extent of ischemically damaged oligodendrocytes, determined by Tau1 immunoreactivity, was reduced in the cerebral cortex by 53% (P = 0.024) in SPD 502-treated rats compared with vehicle-treated rats, but there was minimal effect in the subcortex. The volume of neuronal perikaryal damage after MCA occlusion was significantly reduced by SPD 502 in the cerebral cortex (by 68%; P = 0.005), but there was minimal change in the subcortex with drug treatment. The AMPA receptor antagonist significantly reduced the anatomic extent of lipid peroxidation (assessed as the volume of 4-hydroxynonenol immunoreactivity), and this may have contributed to its ability to protect multiple cell types in ischemia. The data demonstrate that AMPA blockade protects both grey and white matter from damage induced by transient focal ischemia.