The Neurotoxicity of DOPAL: Behavioral and Stereological Evidence for Its Role in Parkinson Disease Pathogenesis

BACKGROUND: The etiology of Parkinson disease (PD) has yet to be fully elucidated. We examined the consequences of injections of 3,4-dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite of dopamine, into the substantia nigra of rats on motor behavior and neuronal survival. METHODS/PRINCIPAL FINDINGS: A total of 800 nl/rat of DOPAL (1 µg/200 nl) was injected stereotaxically into the substantia nigra over three sites while control animals received similar injections of phosphate buffered saline. Rotational behavior of these rats was analyzed, optical density of striatal tyrosine hydroxylase was calculated, and unbiased stereological counts of the substantia nigra were made. The rats showed significant rotational asymmetry ipsilateral to the lesion, supporting disruption of dopaminergic nigrostriatal projections. Such disruption was verified since the density of striatal tyrosine hydroxylase decreased significantly (p<0.001) on the side ipsilateral to the DOPAL injections when compared to the non-injected side. Stereological counts of neurons stained for Nissl in pars compacta of the substantia nigra significantly decreased (p<0.001) from control values, while counts of those in pars reticulata were unchanged after DOPAL injections. Counts of neurons immunostained for tyrosine hydroxylase also showed a significant (p=0.032) loss of dopaminergic neurons. In spite of significant loss of dopaminergic neurons, DOPAL injections did not induce significant glial reaction in the substantia nigra. CONCLUSIONS: The present study provides the first in vivo quantification of substantia nigra pars compacta neuronal loss after injection of the endogenous toxin DOPAL. The results demonstrate that injections of DOPAL selectively kills SN DA neurons, suggests loss of striatal DA terminals, spares non-dopaminergic neurons of the pars reticulata, and triggers a behavioral phenotype (rotational asymmetry) consistent with other PD animal models. This study supports the "catecholaldehyde hypothesis" as an important link for the etiology of sporadic PD

Comparative pharmacokinetics of paracetamol (acetaminophen) and its sulphate and glucuronide metabolites in desert camels and goats

Paracetamol was administered at dosages of 5 mg/kg to camels and 10 mg/kg to goats by the intravenous and intramuscular routes, Parent paracetamol had a significantly slower clearance (21.9 +/- 1.4 ml/mL . kg vs, 52.8 +/- 7.3 mL/min . kg) (P < 0.01) in camels than in goats. In camels the predominant metabolite in plasma was the sulphate, although the ratios of glucuronide:paracetamol and sulphate:paracetamol were similar (5.20 +/- 0.50 vs. 6.59 +/- 0.51 following intravenous administration. In goats the glucuronide metabolite was the predominant moiety in plasma, and the area under the curve (AUC) of the sulphate was only 3.39% of that of the glucuronide conjugate. The apparent AUC for paracetamol in the camel following intramuscular administration was larger than that following intravenous administration, however, when the bioavailability (F) was determined, with correction for altered half-life, within the animal and between study phases it was 71 +/- 17% in goats and 105 +/- 26% in camels.Peer reviewe

Nonsteroidal antiinflammatory drugs, acetaminophen, and hypertension

Selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) as well as acetaminophen belong to the most widely prescribed therapeutic agents worldwide. Their efficacy in pain relief notwithstanding, the use of NSAIDs is associated with an increased cardiovascular risk, which can be partly attributed to their blood pressure raising potential. Adequately powered placebo-controlled trials specifically evaluating the cardiovascular safety of NSAIDs vs. selective COX inhibitors are currently underway. This review summarizes the current knowledge on the cardiovascular effects of NSAIDs and acetaminophen, and their potential clinical consequences