Elsevier

Life Sciences

Volume 61, Issue 5, 27 June 1997, Pages 495-502
Life Sciences

DEPLETION OF NIGROSTRIATAL AND FOREBRAIN TYROSINE HYDROXYLASE BY S-ADENOSYLMETHIONINE: A MODEL THAT MAY EXPLAIN THE OCCURRENCE OF DEPRESSION IN PARKINSON'S DISEASE

https://doi.org/10.1016/S0024-3205(97)00409-8Get rights and content

Abstract

The loss of nigrostriatal tyrosine hydroxylase (TH), dopamine and dopaminergic neurons are the major pathology of Parkinson's disease (PD). These catecholaminergic changes are responsible for the symptoms of tremor, hypokinesia and rigidity. Depression is also a major symptom in PD, but the cause is unknown. The impairments of catecholaminergic fibers in the frontal lobe may be involved, because the frontal lobe of the cerebrum is involved in the regulation of mood, and decreased catecholaminergic activity in the frontal lobe is related to behavioral depression. The changes that damage the nigrostriatal dopamine system and induce motor impairments may also damage the forebrain catecholamine fibers and induce depression. It means that manipulations that damage the nigrostriatum (NS) and induce parkinsonism may also deplete TH in the frontal cortex. Such an effect would suggests a basis for the depression seen in PD. The injection of S-adenosyl-L-methionine (SAM), the biological methyl donor, into the brain of rats damaged the NS, depleted TH and caused tremor and hypokinesia. SAM may interfere also with the forebrain TH, which may help to explain the occurrence of depression in PD. Experiments were designed to test such a hypothesis. The results showed that SAM caused a loss of immunoreactive nerve fibers and it decreased the intensity of TH-immunoreactivity (IR) in the frontal cortex. These changes were accompanied with the loss of cells and the depletion of TH-IR from nerve fibers in the SN and the caudate nucleus. Other studies showed that SAM depletes DA and since SAM induces PD-like changes the results may be relevant to the co-occurrence of PD symptoms and depression. A single biological manipulation may impair the nigrostriatal dopaminergic neurons as well as the frontal cortex catecholaminergic fibers.

Section snippets

Materials and Methods

Sprague-Dawley male rats weighing 250–350 g (Harlam Labs, OH) were used in the experiments. The rats were acclimatized for about 1 wk in a colony room with 12-h light and 12-h dark cycle. Water and food were supplied ad libitum. Groups of rats were anesthetized by intraperitoneal injection of chloral hydrate (400 mg/kg). A stainless steel guide cannula was stereotaxically placed in the brain for the injection into the lateral ventricle of each rat. The cannula was affixed with dental cement,

Results

Rats injected with 1 μmole of SAM and sacrificed 3 days later had a reduction of tyrosine hydroxylase (TH)-immunoreactivity (IR) in the substantia nigra (SN) (Fig. 1). The depletion was more pronounced (lower intensity) in the SN ipsilateral to the injected ventricle (Fig. 1D), as compared to the contralateral SN (Fig. 1C). Both SNs of the SAM-injected rat (Fig. 1C and D) showed lower TH-IR than the matching SNs of the PBS controls (Fig. 1A and B). A higher magnification of the SN highlighting

Discussion

The results show that SAM depleted TH in the substantia nigra and the caudate nucleus/neostriatum and in fibers located in the frontal cortex or frontal lobe. The reduction of TH-IR in the caudate nucleus (Fig. 4) was moderate as compared to the dramatic reduction of TH-IR in the SN (Fig. 3). The SN projects to the caudate nucleus and SAM damages SN neurons [13], therefore the moderate reduction of TH-IR in the caudate may indicate an increase of TH transport to the nerve terminals, which

Acknowledgements

This work was supported by RR 03020 and by NIH RO1 No. NS28432 and NS31177.

References (28)

  • C.G CHARLTON et al.

    Pharm. Biochem. Behav.

    (1992)
  • B.G CROWELL et al.

    Behav. Neural. Biol.

    (1993)
  • M.A COLLINS et al.

    Brain Res.

    (1992)
  • O.Z SELLINGER et al.

    Mech. Aging Dev.

    (1988)
  • J MALLET et al.

    Curr Opin Gen Dev

    (1994)
  • J.R. COOPER, F.E. BLOOM And R.H. ROTH, (1986). The Biochemical Basis of Neuropharmacology, Oxford University Press, New...
  • M.A LLOYD et al.

    O, J. Pharmacol. Exp. Ther.

    (1975)
  • T NAGATSU et al.

    Adv. Neurol.

    (1979)
  • W.D RAUSCH et al.

    J. Neurochem.

    (1988)
  • O HONYKIEWICZ

    Pharmacol. Rev.

    (1966)
  • C. TRETIAKOFF, Thesis, Paris (1919). Cited in W. SHULTZ, Prog. Neurol. 18 121–166...
  • C. FOIX and J. NICOLESCO, Masson, Paris (1925). Cited in K. Jellinger, Adv. Neurol. 45 1–18...
  • J.G GREENFIELD et al.

    J. Neurol Neurosurg. Psychiat.

    (1953)
  • J.L CUMMINGS

    Am. J. Psychiat.

    (1992)
  • Cited by (25)

    • Prenatal exposure to methanol as a dopamine system sensitization model in C57BL/6J mice

      2012, Life Sciences
      Citation Excerpt :

      Since it is well known that behavioral deficits are correlated with NSDA damage in PD individuals, Western blot analysis of key enzymes was performed and showed that there was a reduction in both striatal tyrosine hydroxylase (TH) and l-aromatic amino acid decarboxylase (LAAD) (Fig. 4A; B). Tyrosine hydroxylase is the rate limiting enzyme step in the biosynthesis of dopamine (Nagatsu et al., 1964; Levitt et al., 1965) and impairments to nigrostriatal dopaminergic neurons have been correlated with decreases in both TH protein and dopamine levels (Ricaurte et al., 1987; Charlton, 1997; Langston et al., 1999) and play a role in PD pathogenesis. Prenatal MeOH also increased α-synuclein levels in the striatum (Fig. 4F) but the findings did not reach statistical significance.

    • Catechol-O-methyltransferase enzyme. Cofactor S-adenosyl-l-methionine and related mechanisms

      2010, International Review of Neurobiology
      Citation Excerpt :

      Acute oral l-dopa administration has been shown to increase not only plasma l-dopa concentrations but also SAM levels in PD patients on a chronic l-dopa/DDI regimen in the short term (Müller et al., 2005). This confirmed that an upregulation of MAT with a consecutive SAM increase occurs in PD patients after l-dopa intake by circumstantial evidence (Charlton, 1997; Charlton and Crowell, 1995). One may assume based on these findings that this l-dopa-associated SAM increase also centrally occurs either within the brain itself or due to the transfer of SAM over the blood–brain barrier or both.

    • Acute intranigral homocysteine administration produces stereotypic behavioral changes and striatal dopamine depletion in Sprague-Dawley rats

      2006, Brain Research
      Citation Excerpt :

      A number of previous studies have reported findings that suggested neurotoxicity of homocysteine towards dopaminergic neurons. Administration of SAM, the endogeneous precursor of homocysteine, induced PD-like changes in rats including tremor, rigidity, hypokinesia, striatal DA depletion, and loss of tyrosine hydroxylase immunoreactivity (Charlton, 1997; Charlton and Crowell, 1995). Yet another report demonstrated increased dopaminergic toxicity of the parkinsonian neurotoxin, MPTP in mice treated with homocysteine (Duan et al., 2002).

    View all citing articles on Scopus
    View full text