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Nature of DSP-4-Induced Neurotoxicity

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Handbook of Neurotoxicity

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Abstract

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) is a noradrenergic neurotoxin which selectively damages noradrenergic projections originating from the locus coeruleus (LC) and transiently alters sympathetic neurons in the periphery. The neurotoxin produces chronic brain inflammation that is continuously observed in all brain regions innervated by LC. DSP-4 accumulates intraneuronally and produces nerve terminal degeneration. DSP-4 inhibits norepinephrine (NE) reuptake, stimulates NE release, and increases NE turnover rate. Systemic administration of DSP-4 has a rapid dose-dependent depleting effect on the endogenous NE level. The effect of DSP-4 is largely restricted to noradrenergic neurons; however, DSP-4 slightly reduces the level of 5-hydroxytryptamine and dopamine. The rat age at the time of DSP-4 injection is important in determining the nature of the long-term changes in the noradrenergic system. Thus, DSP-4 treatment of adult rats produces morphological changes of NE neurons with a pronounced decrease in NE levels in the cerebral cortex, hippocampus, spinal cord, and cerebellum. This process is not long-lasting, and after several months, a regeneration of NE nerve terminals is observed. DSP-4 injected to newborn rats induces an alteration of the postnatal development of noradrenergic system with a permanent NE denervation in brain areas distal to LC (cortex and hippocampus) and a hyperinnervation in regions proximal to LC (brainstem, cerebellum, and pons-medulla). This type of hyperinnervation does not exist after DSP-4 treatment of adult animals. The noradrenergic lesion obtained with DSP-4 is highly reproducible; therefore, DSP-4 may represent a suitable tool to discern LC neuron degeneration and recovery and to investigate the projections of non-coerulean NE neurons.

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Abbreviations

5-HIAA:

5-hydroxyindoleacetic acid

5-HT:

serotonin

AD:

aldehyde dehydrogenase

AR:

aldehyde reductase

CNS:

central nervous system

COMT:

catechol-O-methyl transferase

DA:

dopamine

DAT:

dopamine transporter

DBH:

dopamine-β-hydroxylase

DHPG:

3,4-dihydroxyphenylethylene glycol

DOPAC:

3,4-dihydroxyphenylacetic acid

DSP-4:

N-(2-chloroethyl)-N-ethyl-2-bromo-benzylamine

GABA:

γ-aminobutyric acid

i.p.:

intraperitoneal injection

i.v.:

intravenous injection

LC:

locus coeruleus

MAO:

monoamine oxidase

MHPG:

3-methoxy-4-hydroxyphenylethylene glycol

NE:

norepinephrine

NET:

norepinephrine transporter

OCTs:

organic cation transporters

s.c.:

subcutaneous injection

SERT:

serotonin transporter

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Authors and Affiliations

  1. Department of Neurology, Neurosurgery and Biomedical Engineering, Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    Aleksandra Bortel

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  1. Aleksandra Bortel
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Correspondence to Aleksandra Bortel .

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  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Bortel, A. (2022). Nature of DSP-4-Induced Neurotoxicity. In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_75

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