Recombinant AAV8-mediated intrastriatal gene delivery of CDNF protects rats against methamphetamine neurotoxicity

Int J Med Sci. 2017 Mar 17;14(4):340-347. doi: 10.7150/ijms.18623. eCollection 2017.

Abstract

Methamphetamine (METH) exerts significant neurotoxicity in experimental animals and humans when taken at high doses or abused chronically. Long-term abusers have decreased dopamine levels, and they are more likely to develop Parkinson's disease (PD). To date, few medications are available to treat the METH-induced damage of neurons. Glial cell line-derived neurotrophic factor (GDNF) has been previously shown to reduce the dopamine-depleting effects of neurotoxic doses of METH. However, the effect of cerebral dopamine neurotrophic factor (CDNF), which has been reported to be more specific and efficient than GDNF in protecting dopaminergic neurons against 6-OHDA toxicity, in attenuating METH neurotoxicity has not been determined. Thus, the present study aimed to evaluate the neuroprotective effect of CDNF against METH-induced damage to the dopaminergic system in vitro and in vivo. In vitro, CDNF protein increased the survival rate and reduced the tyrosine hydroxylase (TH) loss of METH-treated PC12 cells. In vivo, METH was administered to rats following human CDNF overexpression mediated by the recombinant adeno-associated virus. Results demonstrated that CDNF overexpression in the brain could attenuate the METH-induced dopamine and TH loss in the striatum but could not lower METH-induced hyperthermia.

Keywords: Adeno-associated virus; CDNF; Dopamine.; Methamphetamine; Neuroprotection; Neurotoxicity.

MeSH terms

  • Animals
  • Corpus Striatum / drug effects
  • Corpus Striatum / pathology
  • Dopamine / metabolism
  • Fever / chemically induced
  • Fever / drug therapy
  • Fever / genetics
  • Gene Transfer Techniques*
  • Genetic Therapy
  • Humans
  • Methamphetamine / toxicity*
  • Nerve Growth Factors / genetics*
  • Nerve Growth Factors / therapeutic use
  • Neurons / drug effects
  • Neurons / pathology
  • Neurotoxicity Syndromes / genetics
  • Neurotoxicity Syndromes / pathology
  • Neurotoxicity Syndromes / therapy*
  • PC12 Cells
  • Rats
  • Tyrosine 3-Monooxygenase / genetics

Substances

  • CDNF protein, rat
  • Nerve Growth Factors
  • Methamphetamine
  • Tyrosine 3-Monooxygenase
  • Dopamine