preproenkephalin and Cognition-Disorders

Chronic inflammation may contribute to neuropsychological impairments in individuals with HIV, and modulation of this inflammatory response by opiate receptor ligands is important in light of the prevalence of drug use in HIV populations. Exogenous MOR and KOR agonists have differential effects on central nervous system (CNS) immunity and, while some data suggest KOR agonists are immunosuppressive, the KOR agonist dynorphin has been shown to stimulate human monocyte chemotaxis. In this study, we examined mRNA levels of endogenous opioid receptors OPRK1 and OPRM1, prodynorphin (PDYN), macrophage scavenger receptor CD163, and microglia/macrophage marker CD68 in the caudate and anterior cingulate of postmortem brains from HIV-positive and HIV-negative subjects. Brain tissues of HIV-infected (n = 24) and control subjects (n = 15) were obtained from the Manhattan HIV Brain Bank. Quantification of the gene mRNA was performed using SYBR Green RT-PCR. CD68 and CD163 were increased in HIV-positive (HIV+) compared to HIV-negative (HIV-) individuals in both brain regions. There were higher OPRK1 (P <0.005), and lower PDYN mRNA (P <0.005) levels in the anterior cingulate of HIV+ compared to HIV- subjects. This difference between the clinical groups was not found in the caudate. There was no difference in the levels of OPRM1 mRNA between HIV+ and HIV- subjects. Using linear regression analysis, we examined the relationship of OPRK1 and PDYN mRNA levels in the HIV+ subjects with seven cognitive domain T scores of a neuropsychological test battery. Within the HIV+ subjects, there was a positive correlation between anterior cingulate PDYN mRNA levels and better T-scores in the motor domain. Within the HIV+ subjects there were also positive correlations of both OPRK1 and PDYN mRNA levels with the anti-inflammatory marker CD163, but not with proinflammatory CD68 levels. In this setting, decreased PDYN mRNA may reflect a homeostatic mechanism to reduce monocyte migration, accompanied by compensatory increases in the cognate receptor (KOR) to dampen pro-inflammatory responses. It is possible that enhanced neuroprotection and better motor performance are associated with higher levels of dynorphin and the recruitment of neuroprotective CD163-positive macrophages. Further studies are needed to test this hypothesis.

Topics: Adult; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cognition Disorders; Diagnosis; Encephalitis; Enkephalins; Female; Gene Expression Regulation; Gyrus Cinguli; HIV Infections; Humans; Male; Middle Aged; Neuropsychological Tests; Protein Precursors; Receptors, Cell Surface; Receptors, Opioid, kappa; RNA, Messenger

Expression of dynorphin, an endogenous opioid peptide, increases with age and has been associated with memory impairments in rats. In human, prodynorphin (Pdyn) gene polymorphisms might be linked to cognitive function in the elderly. Moreover, elevated dynorphin levels have been reported in postmortem samples from Alzheimer's disease patients. However, the cellular and molecular processes affected by higher dynorphin levels during aging remain unknown. Using Pdyn(-/-) mice, we observed significant changes in the function and expression of Group 1 metabotropic glutamate receptor (mGluR). Compared with age-matched wild-type (WT) littermates, we found increased expression of mGluR1α and mGluR5 in the hippocampus and cortex of old, but not young, Pdyn(-/-) mice. Increased Group 1 mGluR expression in aged Pdyn(-/-) mice was associated with enhanced mGluR-mediated long-term depression, a form of synaptic plasticity. Notably, whereas aged WT mice developed spatial and recognition memory deficits, aged Pdyn(-/-) mice performed similarly as young mice. Pharmacological treatments with 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, a positive modulator of mGlu5 receptors, or norbinaltorphimine, an antagonist for dynorphin-targeted κ-opioid receptor, rescued memory in old WT mice. Conversely, mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride impaired spatial memory of old Pdyn(-/-) mice. Intact cognition in aged Pdyn(-/-) mice paralleled with increased expression of Group 1 mGluR-related genes Homer 1a and Arc. Finally, aged Pdyn(-/-) mice displayed less anxiety-related behaviors than age-matched WT mice. Together, our results suggest that elevated Pdyn expression during normal aging reduces mGluR expression and signaling, which in turn impairs cognitive functions and increases anxiety.

Topics: Aging; Animals; Anxiety; Benzamides; Benzphetamine; Central Nervous System Stimulants; Cerebral Cortex; Cognition Disorders; Disease Models, Animal; Enkephalins; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Hippocampus; In Vitro Techniques; Long-Term Synaptic Depression; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Precursors; Pyrazoles; Pyridines; Receptors, Metabotropic Glutamate; Recognition, Psychology

Changes in synapse structure occur in frontal neocortex with HIV encephalitis (HIVE) and may contribute to HIV-associated neurocognitive disorders (HAND). A postmortem survey was conducted to determine if mRNAs involved in synaptic transmission are perturbed in dorsolateral prefrontal cortex (DLPFC) in subjects with HIVE or HAND. Expression of the opioid neurotransmitter preproenkephalin mRNA (PENK) was significantly decreased in a sampling of 446 brain specimens from HIV-1 infected people compared to 67 HIV negative subjects. Decreased DLPFC PENK was most evident in subjects with HIVE and/or increased expression of interferon regulatory factor 1 mRNA (IRF1). Type 2 dopamine receptor mRNA (DRD2L) was decreased significantly, but not in the same set of subjects with PENK dysregulation. DRD2L downregulation occurred primarily in the subjects without HIVE or neurocognitive impairment. Subjects with neurocognitive impairment often failed to significantly downregulate DRD2L and had abnormally high IRF1 expression.. Dysregulation of synaptic preproenkephalin and DRD2L in frontal neocortex can occur with and without neurocognitive impairment in HIV-infected people. Downregulation of DRD2L in the prefrontal cortex was associated with more favorable neuropsychological and neuropathological outcomes; the failure to downregulate DRD2L was significantly less favorable. PENK downregulation was related neuropathologically to HIVE, but was not related to neuropsychological outcome independently. Emulating endogenous synaptic plasticity pharmacodynamically could enhance synaptic accommodation and improve neuropsychological and neuropathological outcomes in HIV/AIDS.

Topics: Adult; AIDS Dementia Complex; Antiretroviral Therapy, Highly Active; Cognition Disorders; Encephalitis; Enkephalins; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Prefrontal Cortex; Protein Precursors; Receptors, Dopamine D2; Synapses

Cognitive functions show large variation in elderly people and are substantially heritable. Animal studies revealed that dynorphins influence cognition and memory, especially in aged animals. Thus, we tested the effect of four SNPs (rs7272891, rs1997794, rs2235751 and rs910080) and the VNTR promoter polymorphism in the prodynorphin gene (PDYN) on episodic memory and verbal fluency in a large (n = 1619) sample of elderly people (mean age: 80 +/- 3.39 years; range 75-90 years) recruited through the German study on ageing, cognition and dementia in primary care patients (AgeCoDe). We found that carriers of the minor alleles of rs1997794 (P < 0.002) and rs910080 (P < 0.005) presented with higher episodic memory scores than homozygote carriers of the major allele. Also, a three marker haplotype including these two SNPs and rs2235751 was associated with better episodic memory scores. Verbal fluency scores were non-significantly better in carriers of these respective alleles. Thus, our results suggest a role of PDYN gene variations in determining memory function also in elderly humans.

Topics: Aged; Aged, 80 and over; Cognition; Cognition Disorders; DNA Mutational Analysis; Enkephalins; Female; Gene Frequency; Genetic Markers; Genetic Predisposition to Disease; Genetic Testing; Genotype; Heterozygote; Humans; Male; Memory; Memory Disorders; Minisatellite Repeats; Neuropsychological Tests; Polymorphism, Genetic; Protein Precursors; Verbal Behavior