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Mice and rats have been found almost equally susceptible to (R, S)-alpha-chlorohydrin neurotoxicity, but in rats the distribution of lesions in the neuraxis is less widespread. The topography of the brain lesions shows an incomplete relationship to the regional hierarchy of local glucose utilization in rats and local cerebral blood flow in mice, suggesting that other, unknown, factors also play roles in determining this. Evidence suggesting progressive tonotopic selective vulnerability was found in inferior colliculi in rats given five doses of 50 mg/kg/day. Distinct differences in the patterns of damage to brain stem centres found with chlorohydrin by comparison with other acute energy deprivation syndromes, despite the proximity of the metabolic lesions along the energy generation pathway, suggests there are other unrecognized factors that play a role in determining whether a neuronal centre is at risk or not.

Mice and rats are found to be equally susceptible to developing symmetrical brain stem lesions on exposure to alpha-chlorohydrin and in both species the earliest neurotoxic changes are strictly confined to glial cells, particularly astrocytes; haemorrhages are not found in either species. Minimal evidence of increased vascular leakage of horse-radish peroxidase (HRP) in rats is shown by increased HRP content of perivascular cells within the lesions. Later macrophage invasion and capillary proliferation is accompanied by rare focal leakiness of HRP. Gross astrocytic damage, therefore, does not necessarily impair integrity of the blood-brain barrier. While early in intoxication, astrocytes are severely distended with fluid and their organelles seriously disorganized, they do not die but rapidly regenerate their processes. They thus appear to undergo a process of 'clasmatodendrosis' from which they recover. Comparisons are made with the genesis of symmetrical brain stem lesions in other acute energy deprivation syndromes, including Wernicke's encephalopathy.

Using a 3 x 10 mg/kg dose schedule of 1,3-dinitrobenzene (DNB) over two days in Fischer rats, we have found the following changes in vascular function and structure during the early phase of the symmetrical brain stem lesions. 1. Marked increase in cerebral blood flow generally but especially in the inferior colliculi, from 6 h after the final dose of DNB. 2. Increasing incidence of petechial haemorrhages in inferior colliculi, cerebellar roof, vestibular and superior olivary nuclei from 12 h. 3. Focal leakage of horseradish peroxidase and many sleeve-like arteriolar haemorrhages seen in vibratome sections and by scanning electron microscopy (SEM) in these regions from 12 h. 4. Periarteriolar oedema and protein leakage present in step-serial sections in these regions from 12 h, with astrocyte swelling and occasional small infarcts. These changes suggest that the vascular bed may play an important role in the pathogenesis of these lesions, perhaps in parallel with early astroglial damage. They are discussed in relation to (i) the known presence of xanthine oxidase in the vascular bed of the brain and the likelihood of "useless redox cycling' with free radical generation from this enzyme's interaction with nitroheterocyclic compounds, and (ii) the possible role of free radical damage to endothelial cells in this intoxication and in the analogous lesions of natural and experimental Wernicke's encephalopathy.

Both the racemate and the L-form of BMAA (beta-methylaminoalanine), when injected intraperitoneally into young rats, produced acute signs of cerebellar dysfunction and degeneration of cerebellar stellate, basket, Purkinje and Golgi cells, but not granule cells. Degenerative changes were also occasionally seen in cerebellar roof nuclei which may be secondary in nature. No other changes were found in the remainder of the central nervous system. The doses of the L-form of BMAA producing these changes were from 6 to 14 mumols/g body weight, i.e. the lower and upper levels of the dose range used by Vega and Bell (1967) and equivalent to 75 and 183 mg/rat. Doses of 1 to 4 mg/g body weight of the racemate were given to young rats less than 100 g in weight, but no changes were apparent after daily doses of the racemate of 0.5 mg/g body weight. Damage to cerebellar neurons is considered to be the result of excitotoxic activity. All cells showing degeneration are GABAergic, although not all are known to possess N-methyl-D-aspartate (NMDA) receptors. The present finding of selective cerebellar neuron damage may not conflict with the earlier findings of others, but our results suggest that L-BMAA has unusual glutamate receptor binding properties.

The enzymes beta-glucuronidase and acid phosphatase have been assayed by histochemical and by fluorimetric methods above and below a tightly tied ligature on the rat sciatic nerve over the subsequent 10 days. These findings have been compared with similarly treated animals also given four daily doses of acrylamide (50 mg/kg). The following have been found: 1 during this time, acrylamide at this dose causes slight increases in beta-glucuronidase in untied sciatic nerves, detectable both histochemically and fluorimetrically; 2 below the ligature both enzyme activities were greatly increased and this was slightly reduced in the acrylamide-dosed animals; 3 there was a mild rise in beta-glucuronidase activity in the 1.0 cm above the ligature in undosed animals demonstrable both histochemically and fluorimetrically; 4 that in the acrylamide-dosed animals there was a marked rise in beta-glucuronidase activity both 1.0 cm and 2.0 cm above the ligature which was intensified at 7 days and at 10 days after dosing. This was demonstrated both histochemically and fluorimetrically. These results are discussed in the light of the known sheath cell and axonal responses to acrylamide intoxication.