δ-Opioid Receptor Improves Cognitive Dysfunction In Parkinson’s Disease Through The CAMP-PKA-CREB Pathway

Background and Objective: Parkinson disease(PD)is a common neurodegenerative disease among middle-aged and elderly people.It can be clinically manifested as motor symptoms and non-motor symptoms.The pathogenesis is not yet clear,and the cause of the clinical heterogeneity of PD cognitive dysfunction is not clear.According to the current research,the causes of this kind of heterogeneity are classified as follow: it might due to the neuropathological lesions such as the formation of lewy bodies;the genetic abnormalities such as α-synuclein gene mutations resulting in the formation of α-synuclein oligomers could be one cause as well;or the cumulative damage of multiple neurochemical systems such as opioid peptides,calcium gene-related peptides,cholinergic and dopaminergic neurotransmitters and neuropeptide.Exploring the mechanism of the occurrence and development of PD cognitive impairment will help changing the natural course of the disease,provide ideas for new treatment options,and lay the foundation for disease modification treatment of PD cognitive dysfunction.In this experiment,MPTP was used to construct a mouse model of PD,to explore the protective effect of delta-opioid receptors on dopaminergic neurons in PD model,and to explore its possibility mechanism of action through the c AMP-PKA-CREB pathway.method: Animal experiment: C57BL6 mice were randomly divided into four groups: blank group,model group,delta-opioid receptor agonist(DADLE)intervention group,delta-opioid receptor antagonist(naltrindole)intervention group.Open field,Hanging tail,and water maze experiments were used to detect motor function,cognitive function and emotional disorders in mice.Western blotting detected the expression of opioid receptor agonists and antagonists on the striatum,DOR,PKA,P-CREB,and BDNF of each group of PD mice at the protein level.Real-time fluorescent quantitative PCR studies the effects of opioid receptor agonists and antagonists on the expression of α-synuclein gene mRNA in the striatum of PD mice at the genetic level.The TUNEL method observes the apoptosis of the striatal neurons in mice treated with opioid receptor agonists and antagonists at the cellular level.result:(1)Compared with the model group,mice in the delta-opioid receptor agonist intervention group have improved cognitive function,showing a good neuroprotective effect on the delta-opioid receptor agonist PD.(2)The activation of striatal delta-opioid receptors can reduce the number of apoptotic cells in the striatum of MPTP-PD mice and improve the neuronal apoptosis of the striatum.(3)The activation of DOR in the striatum of MPTP-PD mice increases the expression of BDNF(brain-derived neurotrophic factor)in the brain,thereby showing a protective effect on PD.(4)Compared with the model group,the expression of PKA(c AMP-dependent protein kinase)and p-CERB(phosphorylated cyclic adenosine responsive element binding protein)of the mice in the delta-opioid receptor agonist intervention group was increased,suggesting striae The δ-opioid receptors of the morphology may exert neuroprotective effects by activating the c AMP-PKA-CREB signaling pathway.(5)The activation of δ-opioid receptors may affect the mRNA expression of α-synuclein and tau genes,thereby delaying the progression of PD disease.in conclusion: The activation of δ-opioid receptors has a protective effect on MPTP-induced PD model neurons.The mechanism may be through the activation of the c AMP-PKA-CREB signaling pathway to enhance the expression of BDNF in the brain and affect α-synuclein mRNA expression of genes.