Prevention by the NMDA receptor antagonist, MK801 of neuronal loss produced by tetanus toxin in the rat hippocampus

Abstract

The behavioural and neuropathological effects of tetanus toxin, microinjected directly into the hippocampus, were studied in rats. A single dose (1000 minimum lethal doses, MLDs) of tetanus toxin, injected unilaterally into the hippocampus produced a time‐dependent neuronal loss in the CA1 pyramidal cell layer. In comparison with the contralateral, untreated side these effects became statistically significant (P > 0.05) 7 days (22.0 ± 1.1% reduction) and 10 days (29.2 ± 1.7% reduction) after the injection. No significant changes were observed 7 days after treatment with 500 MLDs whereas a reduction of 37.5 ± 3.1% in the CA1 area cell number was produced 4 days after the injection of 2000 MLDs. Behavioural stimulatory effects were also induced by tetanus toxin (1000 MLDs) within 48 h of the injection and these culminated in generalized convulsions 5–7 days later. Convulsions were observed after a shorter period of latency in rats receiving 2000 MLDs tetanus toxin whereas 500 MLDs were ineffective. No behavioural and neuropathological effects were observed in rats treated with neutralized tetanus toxin (1000 MLDs), bovine serum albumin or phosphate buffer. Pretreatment with MK801 (0.3 mg kg−1, i.p., given 1 h before and after the injection with tetanus toxin and then once daily for 4 or 7 days) prevented the behavioural and neuropathological effects induced by tetanus toxin (1000–2000 MLDs). In addition, such treatment fully protected the animals from the lethal effects induced by 1000 MLDs tetanus toxin. By contrast, pretreatment with diazepam (3.0 mg kg−1, i.p.) using the same schedule as for MK801 did not antagonize the effects of tetanus toxin (1000–2000 MLDs). In conclusion, the present experiments have demonstrated that the intrahippocampal injection of tetanus toxin produces in rats a dose‐ and time‐dependent behavioural stimulation and neuronal loss in the CA1 pyramidal cell layer which can be prevented by the non‐competitive NMDA antagonist, MK801.

Inorganic mercury modifies Ca2+ signals, triggers apoptosis and potentiates NMDA toxicity in cerebellar granule neurons

“…The latter in turn trigger further Ca 2+ influx through NMDA-receptors to reach a sustained, cytotoxic [Ca 2+ ] i level. This model is consistent with other observations in our laboratory using donors of nitric oxide as pro-oxidants (Bonfoco et al, 1996, Leist M. and Nicotera P. unpublished observations) or with other observations in models of hypoxia (Drejer et al, 1985), hypoglycemia (Wieloch, 1985), or various intoxications (Bagetta et al, 1990;Ishimaru et al, 1992), where release of glutamate plays an important role.…”

Peroxynitrite and Nitric Oxide Donors Induce Neuronal Apoptosis by Eliciting Autocrine Excitotoxicity

“…In several pathological situations, e.g. hypoxia (Rothman, 1984;Drejer et al, 1985), hypoglycaemia (Wieloch, 1985;Sandberg et al, 1986) and various forms of intoxication (Bagetta et al, 1990;Turski et al, 1991;Ishimaru et al, 1992), unbalanced release of excitatory neurotransmitters seems to contribute significantly to toxicity, since NMDA receptor antagonists have proved to be neuroprotective. In line with such findings, we have shown (Bonfoco et al, 1996) that inhibitors of NMDA receptors [MK-801 and ~-2-amino-5-phosphonovalenc acid (APV)] prevent the characteristic series of events leading to the apoptosis of CGC after exposure to S-nitrosocysteine or S-nitrosoacetyl-penicillamine (SNAP).…”

Involvement of a Glutamatergic Mechanism in δ‐Dendrotoxin‐Induced Hippocampal Neuronal Cell Loss in the Rat

“… Photomicrographs of rat hippocampal sectors showing the neurodegenerative effects of δ‐dendrotoxin administered into one CA1 region. Rats were injected with either 105 pmol bovine serum albumin (A), 3.5 pmol (B) or 35 pmol δ‐dendrotoxin (C) into one side (T) of the hippocampal formation; 24 hr later, 10 μm coronal sections were cut and stained with cresyl fast violet, as described in detail previously (Bagetta et al 1990). Note that (B; T and C) 3.5 pmol δ‐dendrotoxin caused bilateral neuronal loss limited to the CA1 pyramidal cell layer whereas (C; T and C) the higher dose of the toxin used caused, additionally, neuronal loss in the CA3 and CA4 pyramidal regions of the hippocampus; the samples treated with bovine serum albumin (A; T and C) appeared normal.…”

“…Male Wistar rats (280–300 g) were anaesthetised with chloral hydrate (400 mg/kg, intraperitoneally) and the chronic implantation of a guide cannula into one dorsal hippocampus was carried out under stereotaxic guidance (coordinates: AP=4.0 mm from the bregma, L=2.0 mm from the midline; V=2.4 mm below the dura mater ), as described previously (Bagetta et al 1990). The tip of the cannula was placed 2 mm above the desired area.…”

“…Serial coronal brain tissue sections (10 μm), cut from wax‐embedded tissue blocks, were stained with cresyl fast violet and analyzed by light microscopy (Leitz Orthoplan). Quantitation of neuronal cells was performed in the CA1, CA3 and CA4 pyramidal cell layer and dentate gyrus granule cell layer of the hippocampal formation, as detailed elsewhere (Bagetta et al 1990). Briefly, a 3700 μm 2 grid was positioned on identical regions of either hippocampi in each section (40× objective) and the cells counted in the treated or control (untreated, contralateral) side of each brain section (n=6 per brain; 4–8 rats per group).…”