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DSP4, a Selective Neurotoxin for the Locus Coeruleus Noradrenergic System. A Review of Its Mode of Action

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Abstract

DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) is a selective neurotoxin for the locus coeruleus noradrenergic system in the rodent and bird brain. It readily passes the blood–brain barrier and cyclizes to a reactive aziridinium derivative that is accumulated into the noradrenergic nerve terminals via the noradrenaline transporter. DSP4 is also an irreversible inhibitor of this transporter. Within the nerve terminals the aziridinium derivative reacts with unknown vital cellular components, destroying the terminals. At the dose 50 mg/kg i.p. this is characterized by a rapid and long-lasting loss of noradrenaline and a slower decrease in the dopamine-β-hydroxylase enzyme activity and immunoreactivity in the regions innervated from locus coeruleus. The tissue level of noradrenaline is reduced to 10–30 % of the normal value. The extraneuronal concentration is, on the other hand, increased due to inflow from non-lesioned regions. Like the peripheral sympathetic nerves the non-locus coeruleus noradrenergic systems in the rodent brain is resistant to the neurotoxic action of DSP4. Serotoninergic and dopaminergic nerves are only slightly or not at all affected by DSP4. The neurotoxic effect is counteracted by pretreatment with noradrenaline uptake inhibitors (e.g., desipramine). MAO-B inhibitors of the N-propargylamine type (e.g., selegiline) also counteract the DSP4-induced neurotoxicity with another, yet unknown mechanism. Because of its selectivity for the locus coeruleus system DSP4 is a useful tool in studies of the functional role of this noradrenergic system in the brain.

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Notes

  1. Why the name DSP4? At that time the Astra chemists named their new substances with a three-letters code which was characteristic of each series of compounds. In this case: D is for Dahlbom, Richard, the chemist, S for Svante Ross, P for Psychopharmacology, the intended use, and this compound was the fourth in the series, including intermediates.

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  1. Carina Stenfors

    Present address: Orion Corporation, Orion Pharma, Tengstrominkatu 8, 20101, Turku, Finland

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  1. AstraZeneca R&D, Södertälje, Sweden

    Svante B. Ross & Carina Stenfors

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  2. Carina Stenfors
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Correspondence to Carina Stenfors.

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Ross, S.B., Stenfors, C. DSP4, a Selective Neurotoxin for the Locus Coeruleus Noradrenergic System. A Review of Its Mode of Action. Neurotox Res 27, 15–30 (2015). https://doi.org/10.1007/s12640-014-9482-z

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