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1.
J Neurosci ; 38(18): 4288-4300, 2018 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-29632166

RESUMEN

HIV-associated neurocognitive disorders (HANDs) share common symptoms with Alzheimer's disease (AD), which is characterized by amyloid-ß (Aß) plaques. Plaques are formed by aggregation of Aß oligomers, which may be the toxic species in AD pathogenesis, and oligomers are generated by cleavage of amyloid precursor protein (APP) by ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 inhibitors reverse neuronal loss and cognitive decline in animal models of AD. Although studies have also found evidence of altered APP processing in HIV+ patients, it is unknown whether increased BACE1 expression or Aß oligomer production is a common neuropathological feature of HAND. Moreover, it is unknown whether BACE1 or APP is involved in the excitotoxic, NMDAR-dependent component of HIV-associated neurotoxicity in vitro Herein, we hypothesize that HIV-associated neurotoxicity is mediated by NMDAR-dependent elevation of BACE1 and subsequent altered processing of APP. Supporting this, we observed elevated levels of BACE1 and Aß oligomers in CNS of male and female HIV+ patients. In a model of HIV-associated neurotoxicity in which rat neurons are treated with supernatants from HIV-infected human monocyte-derived macrophages, we observed NMDAR-dependent elevation of BACE1 protein. NMDA treatment also increased BACE1 and both pharmacological BACE1 inhibition and genetic loss of APP were partially neuroprotective. Moreover, in APP knock-out (APP-/-) mouse neurons, NMDA-induced toxicity was BACE1 independent, indicating that cytotoxicity of BACE1 is dependent upon APP cleavage. Our findings suggest that increased BACE1 and the resultant Aß oligomer production may contribute to HIV-associated neuropathogenesis and inhibition of BACE1 could have therapeutic potential in HANDs.SIGNIFICANCE STATEMENT HIV-associated neurocognitive disorders (HANDs) represent a range of cognitive impairments affecting ∼50% of HIV+ individuals. The specific causes of HAND are unknown, but evidence suggests that HIV-infected macrophage infiltration into the brain may cause neuronal damage. Herein, we show that neurons treated with conditioned media from HIV-infected macrophages have increased expression of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein implicated in Alzheimer's disease pathogenesis. Moreover, inhibition of BACE1 prevented neuronal loss after conditioned media exposure, but had no effect on HIV-associated neurotoxicity in neurons lacking its cleavage target amyloid precursor protein. We also observed increased BACE1 expression in HIV+ patient brain tissue, confirming the potential relevance of BACE1 as a therapeutic target in HANDs.


Asunto(s)
Complejo SIDA Demencia/genética , Complejo SIDA Demencia/patología , Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Ácido Aspártico Endopeptidasas/genética , Infecciones por VIH/patología , Neuronas/patología , Adulto , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , Femenino , Hipocampo/metabolismo , Humanos , Macrófagos/química , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , N-Metilaspartato/toxicidad , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética
2.
J Neuroimmune Pharmacol ; 13(1): 64-76, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-28861811

RESUMEN

Mounting evidence suggests that antiretroviral drugs may contribute to the persistence of HIV-associated neurocognitive disorders (HAND), which impact 30%-50% of HIV-infected patients in the post-antiretroviral era. We previously reported that two first generation HIV protease inhibitors, ritonavir and saquinavir, induced oxidative stress, with subsequent neuronal death in vitro, which was reversed by augmentation of the endogenous antioxidant response by monomethyl fumarate. We herein determined whether two newer-generation PIs, darunavir and lopinavir, were deleterious to neurons in vitro. Further, we expanded our assessment to include three integrase strand transfer inhibitors, raltegravir, dolutegravir, and elvitegravir. We found that only lopinavir and elvitegravir were neurotoxic to primary rat neuroglial cultures as determined by the loss of microtubule-associated protein 2 (MAP2). Intriguingly, lopinavir but not elvitegravir led to oxidative stress and induced the endogenous antioxidant response (EAR). Furthermore, neurotoxicity of lopinavir was blocked by pharmacological augmentation of the endogenous antioxidant heme oxygenase-1 (HO-1), expanding our previous finding that protease inhibitor-induced neurotoxicity was mediated by oxidative stress. Conversely, elvitegravir but not lopinavir led to increased eIF2α phosphorylation, indicating the activation of a common adaptive pathway termed the integrated stress response (ISR), and elvitegravir-mediated neurotoxicity was partially alleviated by the ISR inhibitor trans-ISRIB, suggesting ISR as a promoter of elvitegravir-associated neurotoxicity. Overall, we found that neurotoxicity was induced only by a subset of protease inhibitors and integrase strand transfer inhibitors, providing evidence for class- and drug-specific neurotoxic effects of antiretroviral drugs. Future in vivo studies will be critical to confirm the neurotoxicity profiles of these drugs for incorporation of these findings into patient management. The EAR and ISR pathways are potential access points for the development of adjunctive therapies to complement antiretroviral therapies and limit their contribution to HAND persistence.


Asunto(s)
Inhibidores de la Proteasa del VIH/toxicidad , Neuronas/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Complejo SIDA Demencia/etiología , Animales , Células Cultivadas , Neuronas/patología , Ratas , Ratas Sprague-Dawley
3.
Springerplus ; 4: 25, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25635245

RESUMEN

Sleep/wake disturbance is a feature of almost all common age-related neurodegenerative diseases. Although the reason for this is unknown, it is likely that this inability to maintain sleep and wake states is in large part due to declines in the number and function of wake-active neurons, populations of cells that fire only during waking and are silent during sleep. Consistent with this, many of the brain regions that are most susceptible to neurodegeneration are those that are necessary for wake maintenance and alertness. In the present review, these wake-active populations are systematically assessed in terms of their observed pathology across aging and several neurodegenerative diseases, with implications for future research relating sleep and wake disturbances to aging and age-related neurodegeneration.

4.
Addict Biol ; 19(3): 338-42, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-23231571

RESUMEN

In rats, reexposure to heroin-paired contexts after extinction of lever responding in a different context reinstates heroin seeking. Previous reports indicate that ventral hippocampus/Ca1 region plays a critical role in cocaine-, cue- and context-induced reinstatement of cocaine seeking. Here, we examined whether ventral subiculum, the output region of ventral hippocampus, is involved in context-induced reinstatement of heroin seeking. We found that reversible inactivation of ventral subiculum, but not posterior Ca1, with the gamma-aminobutyric acid agonists muscimol + baclofen decreased context-induced reinstatement of heroin seeking. Our findings, together with previous studies on cocaine seeking, indicate a critical role of ventral subiculum in context-induced relapse across drug classes.


Asunto(s)
Dependencia de Heroína/fisiopatología , Hipocampo/fisiopatología , Animales , Baclofeno/farmacología , Señales (Psicología) , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Heroína/farmacología , Hipocampo/efectos de los fármacos , Muscimol/farmacología , Narcóticos/farmacología , Ratas , Recurrencia , Autoadministración
5.
Behav Pharmacol ; 24(4): 332-6, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23751516

RESUMEN

The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a neuronal activity-regulated pentraxin (Narp) dominant-negative construct in the mPFC of mice blocked extinction of morphine-conditioned place preference. To further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector expressing a dominant-negative form of Narp (NarpN) into the infralimbic region of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian-conditioned place preference paradigm but not in the operant paradigm of drug self-administration.


Asunto(s)
Proteína C-Reactiva/metabolismo , Extinción Psicológica/efectos de los fármacos , Heroína/administración & dosificación , Narcóticos/administración & dosificación , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Corteza Prefrontal/citología , Análisis de Varianza , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Proteína C-Reactiva/genética , Condicionamiento Clásico/efectos de los fármacos , Dependovirus/genética , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Proteínas del Tejido Nervioso/genética , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Factores de Tiempo , Transducción Genética
6.
J Neurosci ; 32(14): 4982-91, 2012 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-22492053

RESUMEN

In humans, exposure to contexts previously associated with heroin use can provoke relapse. In rats, exposure to heroin-paired contexts after extinction of drug-reinforced responding in different contexts reinstates heroin seeking. This effect is attenuated by inhibition of glutamate or dopamine transmission in nucleus accumbens shell, or inactivation of ventral medial prefrontal cortex (mPFC). Here, we used an anatomical asymmetrical disconnection procedure to demonstrate that an interaction between glutamatergic projections from ventral mPFC to accumbens shell and local dopamine D(1) postsynaptic receptors contributes to context-induced reinstatement of heroin seeking. We also combined the marker of neuronal activity, Fos, with the retrograde tracer Fluoro-Gold to assess activation in this pathway during context-induced reinstatement. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a nondrug-associated context in the presence of the discrete cue. Rats were then tested in the heroin- or extinction-associated contexts under extinction conditions. Injections of muscimol + baclofen into ventral mPFC in one hemisphere and D(1)-family receptor antagonist SCH 23390 into the contralateral or ipsilateral accumbens shell decreased context-induced reinstatement. Unilateral injections of muscimol + baclofen into ventral mPFC or SCH 23390 into the accumbens shell had no effect. Context-induced reinstatement was associated with increased Fos expression in ventral mPFC neurons, including those projecting to accumbens shell, with higher double-labeling in the ipsilateral projection than in the contralateral projection. Our results demonstrate that activation of glutamatergic projections from ventral mPFC to accumbens shell, previously implicated in inhibition of cocaine relapse, promotes heroin relapse.


Asunto(s)
Conducta Adictiva/fisiopatología , Extinción Psicológica/fisiología , Dependencia de Heroína/fisiopatología , Núcleo Accumbens/fisiología , Corteza Prefrontal/fisiología , Animales , Conducta Adictiva/psicología , Extinción Psicológica/efectos de los fármacos , Dependencia de Heroína/psicología , Masculino , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Long-Evans , Autoadministración
7.
J Neurosci ; 31(11): 4251-9, 2011 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-21411666

RESUMEN

Numerous studies with the neural activity marker Fos indicate that cocaine activates only a small proportion of sparsely distributed striatal neurons. Until now, efficient methods were not available to assess neuroadaptations induced specifically within these activated neurons. We used fluorescence-activated cell sorting (FACS) to purify striatal neurons activated during cocaine-induced locomotion in naive and cocaine-sensitized cfos-lacZ transgenic rats. Activated neurons were labeled with an antibody against ß-galactosidase, the protein product of the lacZ gene. Cocaine induced a unique gene expression profile selectively in the small proportion of activated neurons that was not observed in the nonactivated majority of neurons. These genes included altered levels of the immediate early genes arc, fosB, and nr4a3, as well as genes involved in p38 MAPK signaling and cell-type specificity. We propose that this FACS method can be used to study molecular neuroadaptations in specific neurons encoding the behavioral effects of abused drugs and other learned behaviors.


Asunto(s)
Cocaína/farmacología , Cuerpo Estriado/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Genes Inmediatos-Precoces/efectos de los fármacos , Neuronas/efectos de los fármacos , Análisis de Varianza , Animales , Cuerpo Estriado/metabolismo , Femenino , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Inmunohistoquímica , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Transgénicas , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
8.
Nat Neurosci ; 14(4): 420-2, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21336273

RESUMEN

In a rat model of context-induced relapse to heroin, we identified sparsely distributed ventral medial prefrontal cortex (mPFC) neurons that were activated by the heroin-associated context. Selective pharmacogenetic inactivation of these neurons inhibited context-induced drug relapse. A small subset of ventral mPFC neurons formed neuronal ensembles that encode the learned associations between heroin reward and heroin-associated contexts; re-activation of these neuronal ensembles by drug-associated contexts during abstinence provoked drug relapse.


Asunto(s)
Dependencia de Heroína/patología , Heroína/toxicidad , Red Nerviosa/efectos de los fármacos , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Síndrome de Abstinencia a Sustancias/patología , Analgésicos Opioides/toxicidad , Animales , Modelos Animales de Enfermedad , Dependencia de Heroína/metabolismo , Red Nerviosa/patología , Neuronas/patología , Corteza Prefrontal/metabolismo , Ratas , Prevención Secundaria , Síndrome de Abstinencia a Sustancias/metabolismo
9.
Addict Biol ; 16(2): 261-72, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21182575

RESUMEN

Glial cell line-derived neurotrophic factor (GDNF) activity in ventral tegmental area (VTA) mediates the time-dependent increases in cue-induced cocaine-seeking after withdrawal (incubation of cocaine craving). Here, we studied the generality of these findings to incubation of heroin craving. Rats were trained to self-administer heroin for 10 days (6 hours/day; 0.075 mg/kg/infusion; infusions were paired with a tone-light cue) and tested for cue-induced heroin-seeking in extinction tests after 1, 11 or 30 withdrawal days. Cue-induced heroin seeking was higher after 11 or 30 days than after 1 day (incubation of heroin craving), and the time-dependent increases in extinction responding were associated with time-dependent changes in GDNF mRNA expression in VTA and nucleus accumbens. Additionally, acute accumbens (but not VTA) GDNF injections (12.5 µg/side) administered 1-3 hours after the last heroin self-administration training session enhanced the time-dependent increases in extinction responding after withdrawal. However, the time-dependent increases in extinction responding after withdrawal were not associated with changes in GDNF protein expression in VTA and accumbens. Additionally, interfering with endogenous GDNF function by chronic delivery of anti-GDNF monoclonal neutralizing antibodies (600 ng/side/day) into VTA or accumbens had no effect on the time-dependent increases in extinction responding. In summary, heroin self-administration and withdrawal regulate VTA and accumbens GDNF mRNA expression in a time-dependent manner, and exogenous GDNF administration into accumbens but not VTA potentiates cue-induced heroin seeking. However, based on the GDNF protein expression and the anti-GDNF monoclonal neutralizing antibodies manipulation data, we conclude that neither accumbens nor VTA endogenous GDNF mediates the incubation of heroin craving.


Asunto(s)
Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Dependencia de Heroína/fisiopatología , Heroína/toxicidad , Narcóticos/toxicidad , Núcleo Accumbens/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Área Tegmental Ventral/fisiopatología , Animales , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Señales (Psicología) , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Factor Neurotrófico Derivado de la Línea Celular Glial/farmacología , Dependencia de Heroína/psicología , Masculino , Núcleo Accumbens/efectos de los fármacos , ARN Mensajero/genética , Ratas , Ratas Long-Evans , Síndrome de Abstinencia a Sustancias/psicología , Área Tegmental Ventral/efectos de los fármacos
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