Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease

Background: Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress. Results: The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons. Conclusions: Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease

Partial protection by CDP-choline against kainic acid-induced lesion in the rat caudate nucleus.

The acute intraperitoneal administration of CDP-choline to rats caused an increase in striatal dopamine (DA) synthesis, measured by DOPA accumulation after decarboxylase inhibition. Moreover, the chronic treatment with CDP-choline induced a decrease in the total number of 3H-spiroperidol binding sites, while partially antagonizing the disappearance of DA-sensitive adenylate cyclase activity elicited by intrastriatal kainic acid. These results suggest that CDP-choline may have a trophic and/or stimulant action on the function of nigrostriatal dopaminergic neurons

Substantia nigra as an out-put station for striatal dopaminergic responses: role of a GABA-mediated inhibition of pars reticulata neurons.

Intranigral administration of kainic acid results in loss of pars reticulata neurons without damage to axons traversing or terminating within the nigra. Unilateral nigral lesions with kainic acid result in an ipsilateral turning upon administration of apomorphine, a dopamine (DA)-receptor agonist and in contralateral turning upon administration of haloperidol, a DA-receptor blocker. Destruction of post-synaptic structures in the striatum of the side contralateral to that injected with kainic acid results in a drastic reduction, abolition or even reversal of the turning effects elicited by apomorphine and haloperidol. Unilateral intranigral microinjection of nanogram amounts of the GABA-receptor antagonists picrotoxin and bicuculline elicits ipsilateral circling upon apomorphine administration. Kainic-induced lesion or microinjection of picrotoxin or bicuculline in the nigra ipsilateral to a 6-OHDA-lesion of nigro-striatal DA-neurons results in reduction, abolition or reversal of the contralateral circling produced by apomorphine. The results indicate that the nigra pars reticulata is a station for dopaminergic impulses originating from the striatum and suggest that the turning behavior in response to striatal DA-receptor stimulation is due to a GABA-mediated inhibition of ipsiversive pars reticulata neurons

Opposite turning effects of dainic and ibotenic acid injected in the rat substantia nigra

Unilateral intranigral administration of kainic and ibotenic acid, two putative stimulants of glutamatergic mechanisms, elicited turning behaviour starting from doses of 10 ng. While the turning produced by kainic acid was ipsilateral, that produced by ibotenic acid was contralateral to the injected side. Previous destruction of dopaminergic neurons on the side of the intranigral injection failed to reduce the turning behaviour. Peripheral treatment with picrotoxin did not reduce the turning in response to ibotenic acid. The results might suggest the existence of excitatory and inhibitory glutamate receptors which control nigral non-dopaminergic neurons mediating turning-behaviour

Self-inhibitory dopamine-receptors and central effects of apomorphine.

Apomorphine, a central dopamine-receptor agonist, is well known to produce excitatory effects in animals. However, low doses exert depressant effects as hypomotility, sedation and sleep. The mechanism of these effects are discussed in terms of a stimulation by apomorphine of DA-receptors, different from the post-synaptic ones, provided of an inhibitory effect on DA-synthesis and on the firing of dopaminergic neurons

Role of dorsal mesencephalic reticular formation and deep layers of superior colliculus in turning behaviour elicited from the striatum1

Kainate or electrolytic lesions were placed unilaterally in the dorsal mesencephalic reticular formation (MRF) or in the deep layers of the superior colliculus (DLSC) on the same side of a unilateral lesion of the medial forebrain bundle with 6-OHDA. Before the lesions the rats turned contralaterally when challenged with 0.25 mg/kg of apomorphine. After lesions of the MRF most rats turned ipsilaterally in response to the same dose of apomorphine. After lesions of the DLSC apomorphine-induced contralateral turning was significantly reduced but not abolished. The results indicate that the MRF and DLSC play a primary role in the expression of turning originated from the striatum