The effect of striatal pre‐enkephalin overexpression in the basal ganglia of the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson's disease

Abstract

The midbrain dopamine (DA) cell death underlying Parkinson's disease (PD) is associated with upregulation of pre-enkephalin (pENK) in striatopallidal neurons. Our previous results obtained with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonian monkeys suggest that increased striatal expression of pENK mRNA is a compensatory mechanism to alleviate PD-related motor symptoms. In this study, we tested the hypothesis that increased pENK expression in the striatum protects against the neurotoxic insults of MPTP in mice. To this end, recombinant adeno-associated virus serotype 2 also containing green fluorescent protein was used to overexpress pENK prior to DA depletion. Our results showed that overexpression of pENK in the striatum of MPTP mice induced: (i) increased levels of the opioid peptide enkephalin (ENK) in the striatum; (ii) higher densities of ENK-positive fibers in both the globus pallidus (GP) and the substantia nigra; (iii) higher locomotor activity; and (iv) a higher density of striatal tyrosine hydroxylase-positive fibers in the striatum. In addition, striatal overexpression of pENK in MPTP -treated mice led to 52 and 43% higher DA concentrations and DA turnover, respectively, in the GP compared to sham-treated MPTP mice. These observations are in agreement with the idea that increased expression of pENK at an early stage of disease can improve PD symptoms.

Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

“…Similarly, DA antagonists impair MWM learning ( McNamara and Skelton, 1993 ) and transgenic mice lacking DA D1 receptors showed severely impaired MWM acquisition ( Smith et al., 1998 ); and administration of D1 receptor agonists enhanced acquisition performance ( Hersi et al., 1995 ). Likely, administration of smilagenin ( He et al., 2019 ) or overexpression pre-enkephalin in the striatum ( Bissonnette et al., 2014 ) to increase TH positive neurons in SN significantly improved the locomotor ability. Therefore, enhanced noradrenergic and dopaminergic activities resulting from overexpression of these transcription factors in the LC significantly improves the function of the NE and DA systems.…”

miR‐506‐loaded gelatin nanospheres target PENK and inactivate the ERK/Fos signaling pathway to suppress triple‐negative breast cancer aggressiveness

“…PENK is a highly conserved precursor of the opioid pentapeptides Met‐ and Leu‐enkephalin 21 . PENK was reported dysregulated in Alzheimer's, 22 Parkinson's, 23 Schizophrenia's, 24 and Huntington's diseases 25 . PENK could be used as a diagnostic and prognostic indicator for heart failure patients 26 .…”

β-Funaltrexamine Displayed Anti-Inflammatory and Neuroprotective Effects in Cells and Rat Model of Stroke

“…Beyond its effect on the nociceptive/analgesic systems, the opioidergic system also displays effects on physiological and behavioral functions, including respiration, ion channel activity, and immune responses [1,2]. Additionally, alteration in the opioidergic system has been reported in the disease initiation and progression of several acute and chronic diseases, including neurodegenerative diseases [3][4][5][6][7][8][9]. These phenomena highlight the potential pathogenic roles that the opioidergic system may have and candidate targets for intervention with an aim to prevent and/or treat diseases.…”

“…Because the well-known effects of morphine are mediated specifically by the µ opioid receptor subtype, the activation of the µ opioid receptor is closely linked with neuroinflammation. Accordingly, the µ opioid receptor agonists such as d-Ala 2 -MePhe 4 -Glyol 5 -Enkephalin (DAMGO) and fentanyl display pro-inflammatory potential in microglia and astrocytes, while the µ opioid receptor antagonists suppress immune cell activation and pro-inflammatory cytokine expression challenged with morphine, Lipopolysaccharide (LPS), ethanol, or fentanyl [15,17,19,20]. Parallel suppression in inflammatory responses is observed in the presence of δ and κ opioid receptor agonists against LPS or ethanol treatments [20][21][22][23].…”