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1.
Eur J Neurosci ; 59(7): 1441-1459, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38151481

RESUMEN

Dopamine D2 receptor (D2R) is expressed in striatopallidal neurons and decreases forskolin-stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma-aminobutyric acid (GABA) release. Dopamine D3 receptor (D3R) mRNA is expressed in a population of striatal D2R-expressing neurons. Also, D3R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D2R and D3R colocalize in striatopallidal terminals and whether D3R modulates the D2R effect on forskolin-stimulated [3H]cAMP accumulation in pallidal synaptosomes and high K+ stimulated-[3H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D2R and D3R functions; thus, we study whether this system regulates its functional interaction. D2R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K+ decreases it. Both treatments increase the D2R inhibition of forskolin-stimulated [3H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D2R function. Quinpirole also activates D3R, potentiating D2R inhibition of cAMP accumulation in the ophiobolin A-treated synaptosomes. D2R and D3R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM-kinase II alfa (CaMKIIα) immunoprecipitates with D3R and increases after high K+ depolarization. In the presence of KN62, a CaMKIIα blocker, D3R potentiates D2R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D3R function regulation by CaMKIIα. Our data indicate that D3R potentiates the D2R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM-CaMKIIα system.


Asunto(s)
Calmodulina , Receptores de Dopamina D3 , Sesterterpenos , Receptores de Dopamina D3/metabolismo , Quinpirol/farmacología , Calmodulina/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Colforsina , Receptores de Dopamina D2/metabolismo , Ácido gamma-Aminobutírico/metabolismo
2.
Inhal Toxicol ; 35(1-2): 1-13, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36325922

RESUMEN

Alterations in dopaminergic transmission are associated with neurological disorders, such as depression, autism, and Parkinson's disease. Exposure of rats to ambient fine (FP) or ultrafine (UFP) particles induces oxidative and inflammatory responses in the striatum, a neuronal nucleus with dense dopaminergic innervation and critically involved in the control of motor activity.Objectives: We used an ex vivo system to evaluate the effect of in vivo inhalation exposure to FP and UFP on motor activity and dopaminergic transmission.Materials and Methods: Male adult Wistar rats were exposed to FP, UFP, or filtered air for 8 weeks (subchronic exposure; 5 h/day, 5 days/week) in a particle concentrator. Motor activity was evaluated using the open-field test. Uptake and release of [3H]-dopamine were assessed in striatal synaptosomes, and dopamine D2 receptor (D2R) affinity for dopamine was evaluated by the displacement of [3H]-spiperone binding to striatal membranes.Results: Exposure to FP or UFP significantly reduced spontaneous motor activity (ambulatory distance: FP -25%, UFP -32%; ambulatory time: FP -24%, UFP -22%; ambulatory episodes: FP -22%, UFP -30%), decreased [3H]-dopamine uptake (FP -18%, UFP -24%), and increased, although not significantly, [3H]-dopamine release (113.3 ± 16.3 and 138.6 ± 17.3%). Neither FP nor UFP exposure affected D2R density or affinity for dopamine.Conclusions: These results indicate that exposure to ambient particulate matter reduces locomotion in rats, which could be related to altered striatal dopaminergic transmission: UFP was more potent than FP. Our results contribute to the evidence linking environmental factors to changes in brain function that could turn into neurological and psychiatric disorders.HIGHLIGHTSYoung adult rats were exposed to fine (FP) or ultrafine (UFP) particles for 40 days.Exposure to FP or UFP reduced motor activity.Exposure to FP or UFP reduced dopamine uptake by striatal synaptosomes.Neither D2R density or affinity for dopamine was affected by FP or UFP.UFP was more potent than FP to exert the effects reported.


Asunto(s)
Contaminantes Atmosféricos , Material Particulado , Ratas , Masculino , Animales , Material Particulado/toxicidad , Tamaño de la Partícula , Dopamina , Ratas Wistar , Actividad Motora , Contaminantes Atmosféricos/toxicidad
3.
Synapse ; 76(11-12): e22246, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35831708

RESUMEN

Striatal medium-sized spiny neurons express mRNA and protein of GPR55 receptors that stimulate neurotransmitter release; thus, GPR55 could be sent to nigral striatal projections, where it might modulate GABA release and motor behavior. Here, we study the presence of GPR55 receptors at striato-nigral terminals, their modulation of GABA release, their signaling pathway, and their effect on motor activity. By double immunohistochemistry, we found the colocation of GPR55 protein and substance P in the dorsal striatum. In slices of the rat substantia nigra, the GPR55 agonists LPI and O-1602 stimulated [3 H]-GABA release induced by high K+ depolarization in a dose-dependent manner. The antagonists CID16020046 and cannabidiol prevented agonist stimulation in a dose-dependent way. The effect of GPR55 on nigral [3 H]-GABA release was prevented by lesion of the striatum with kainic acid, which was accompanied by a decrement of GPR55 protein in nigral synaptosomes, indicating the presynaptic location of receptors. The depletion of internal Ca2+ stores with thapsigargin did not prevent the effect of LPI on [3 H]-GABA release, but the remotion or chelation of external calcium did. Blockade of Gi, Gs, PLC, PKC, or dopamine D1 receptor signaling proteins did not prevent the effect of GPR55 on release. However, the activation of GPR55 stimulated [3 H]-cAMP accumulation and PKA activity. Intranigral unilateral injection of LPI induces contralateral turning. This turning was prevented by CID16020046, cannabidiol, and bicuculline but not by SCH 23390. Our data indicate that presynaptic GPR55 receptors stimulate [3 H]-GABA release at striato-nigral terminals through [3 H]-cAMP production and stimulate motor behavior.


Asunto(s)
Cannabidiol , Receptores de Cannabinoides , Receptores Acoplados a Proteínas G , Receptores Presinapticos , Animales , Compuestos de Azabiciclo , Benzoatos , Bicuculina/farmacología , Calcio/metabolismo , Cannabidiol/metabolismo , Cannabidiol/farmacología , Ácido Kaínico/metabolismo , Ácido Kaínico/farmacología , Neurotransmisores/farmacología , ARN Mensajero/metabolismo , Ratas , Receptores de Cannabinoides/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Presinapticos/metabolismo , Sustancia P/metabolismo , Sustancia Negra/metabolismo , Tapsigargina/metabolismo , Tapsigargina/farmacología , Ácido gamma-Aminobutírico/metabolismo
4.
Pharmacol Res ; 185: 106476, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36182040

RESUMEN

A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1R and D3R) influences the pharmacological properties of three structurally similar selective dopamine D3R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4-116. By using D1R-D3R heteromer-disrupting peptides, it could be demonstrated that the three D3R ligands display different D1R-D3R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1R-mediated signaling in the D1R-D3R heteromer; PG01037, acting as a D3R antagonist cross-antagonized D1R-mediated signaling in the D1R-D3R heteromer; and VK4-116 specifically acted as a ß-arrestin-biased agonist in the D1R-D3R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3R ligands that are dependent on D1R-D3R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3R ligands in vivo. The results supported the involvement of D1R-D3R heteromers in the locomotor activation by D1R agonists in reserpinized mice and L-DOPA-induced dyskinesia in rats, highlighting the D1R-D3R heteromer as a main pharmacological target for L-DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development.


Asunto(s)
Discinesias , Levodopa , Animales , Ratas , Ratones , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D1/agonistas , Dopamina , Receptores Acoplados a Proteínas G , Ligandos
5.
J Nanobiotechnology ; 20(1): 413, 2022 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-36109747

RESUMEN

Parkinson's disease (PD) significantly affects patients' quality of life and represents a high economic burden for health systems. Given the lack of safe and effective treatments for PD, drug repositioning seeks to offer new medication alternatives, reducing research time and costs compared to the traditional drug development strategy. This review aimed to collect evidence of drugs proposed as candidates to be reused in PD and identify those with the potential to be reformulated into nanocarriers to optimize future repositioning trials. We conducted a detailed search in PubMed, Web of Science, and Scopus from January 2015 at the end of 2021, with the descriptors "Parkinson's disease" and "drug repositioning" or "drug repurposing". We identified 28 drugs as potential candidates, and six of them were found in repositioning clinical trials for PD. However, a limitation of many of these drugs to achieve therapeutic success is their inability to cross the blood-brain barrier (BBB), as is the case with nilotinib, which has shown promising outcomes in clinical trials. We suggest reformulating these drugs in biodegradable nanoparticles (NPs) based on lipids and polymers to perform future trials. As a complementary strategy, we propose functionalizing the NPs surface by adding materials to the surface layer. Among other advantages, functionalization can promote efficient crossing through the BBB and improve the affinity of NPs towards certain brain regions. The main parameters to consider for the design of NPs targeting the central nervous system are highlighted, such as size, PDI, morphology, drug load, and Z potential. Finally, current advances in the use of NPs for Parkinson's disease are cited.


Asunto(s)
Enfermedad de Parkinson , Reposicionamiento de Medicamentos , Humanos , Lípidos , Nanotecnología , Enfermedad de Parkinson/tratamiento farmacológico , Preparaciones Farmacéuticas , Polímeros/uso terapéutico , Calidad de Vida
6.
Eur J Neurosci ; 52(11): 4563-4585, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33098606

RESUMEN

Two major groups of terminals release GABA within the Globus pallidus; one group is constituted by projections from striatal neurons, while endings of the intranuclear collaterals form the other one. Each neurons' population expresses different subtypes of dopamine D2-like receptors: D2 R subtype is expressed by encephalin-positive MSNs, while pallidal neurons express the D4 R subtype. The D2 R modulates the firing rate of striatal neurons and GABA release at their projection areas, while the D4 R regulates Globus pallidus neurons excitability and GABA release at their projection areas. However, it is unknown if these receptors control GABA release at pallido-pallidal collaterals and regulate motor behavior. Here, we present neurochemical evidence of protein content and binding of D4 R in pallidal synaptosomes, control of [3 H] GABA release in pallidal slices of rat, electrophysiological evidence of the presence of D4 R on pallidal recurrent collaterals in mouse slices, and turning behavior induced by D4 R antagonist microinjected in amphetamine challenged rats. As in projection areas of pallidal neurons, GABAergic transmission in pallido-pallidal recurrent synapses is under modulation of D4 R, while the D2 R subtype, as known, modulates striato-pallidal projections. Also, as in projection areas, D4 R contributes to control the motor activity differently than D2 R. This study could help to understand the organization of intra-pallidal circuitry.


Asunto(s)
Globo Pálido , Receptores de Dopamina D4 , Animales , Cuerpo Estriado/metabolismo , Dopamina , Globo Pálido/metabolismo , Ratones , Ratas , Receptores de Dopamina D1/metabolismo
7.
Biochem Biophys Res Commun ; 524(1): 255-261, 2020 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-31983427

RESUMEN

Neurotransmission is one of the most important processes in neuronal communication and depends largely on Ca2+ entering synaptic terminals through voltage-gated Ca2+ (CaV) channels. Although the contribution of L-type CaV channels in neurotransmission has not been unambiguously established, increasing evidence suggests a role for these proteins in noradrenaline, dopamine, and GABA release. Here we report the regulation of L-type channels by Cdk5, and its possible effect on GABA release in the substantia nigra pars reticulata (SNpr). Using patch-clamp electrophysiology, we show that Cdk5 inhibition by Olomoucine significantly increases current density through CaV1.3 (L-type) channels heterologously expressed in HEK293 cells. Likewise, in vitro phosphorylation showed that Cdk5 phosphorylates residue S1947 in the C-terminal region of the pore-forming subunit of CaV1.3 channels. Consistent with this, the mutation of serine into alanine (S1947A) prevented the regulation of Cdk5 on CaV1.3 channel activity. Our data also revealed that the inhibition of Cdk5 increased the frequency of high K+-evoked miniature inhibitory postsynaptic currents in rat SNpr neurons, acting on L-type channels. These results unveil a novel regulatory mechanism of GABA release in the SNpr that involves a direct action of Cdk5 on L-type channels.


Asunto(s)
Canales de Calcio Tipo L/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Potenciales Postsinápticos Inhibidores , Neostriado/metabolismo , Receptores de GABA-A/metabolismo , Sustancia Negra/metabolismo , Animales , Animales Recién Nacidos , Canales de Calcio Tipo L/química , Células HEK293 , Humanos , Masculino , Fosforilación , Ratas Wistar , Ácido gamma-Aminobutírico/metabolismo
8.
Synapse ; 74(7): e22149, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-31975491

RESUMEN

Dopamine (DA) modulates basal ganglia (BG) activity for initiation and execution of goal-directed movements and habits. While most studies are aimed to striatal function, the cellular and molecular mechanisms underlying dopaminergic regulation in other nuclei of the BG are not well understood. Therefore, we set to analyze the dopaminergic modulation occurring in subthalamo-nigral synapse, in both pars compacta (SNc) and pars reticulata (SNr) neurons, because these synapses are important for the integration of information previously processed in striatum and globus pallidus. In this study, electrophysiological and pharmacological evidence of dopaminergic modulation on glutamate release through calcium channels is presented. Using paired pulse ratio (PPR) measurements and selective blockers of these ionic channels, together with agonists and antagonists of DA D2 -like receptors, we found that blockade of the CaV 3 family occludes the presynaptic inhibition produced by the activation of DA receptors pharmacologically profiled as D3 -type in the STh-SNc synapses. On the contrast, the blockade of CaV 2 channels, but not CaV 3, occlude with the effect of the D3 agonist, PD 128907, in the STh-SNr synapse. The functional role of this differential distribution of calcium channels that modulate the release of glutamate in the SN implies a fine adjustment of firing for both classes of neurons. Dopaminergic neurons of the SNc establish a DA tone within the SN based on the excitatory/inhibitory inputs; such tone may contribute to processing information from subthalamic nucleus and could also be involved in pathological DA depletion that drives hyperexcitation of SNr neurons.


Asunto(s)
Canales de Calcio/metabolismo , Neuronas Dopaminérgicas/metabolismo , Sustancia Negra/metabolismo , Subtálamo/metabolismo , Potenciales Sinápticos , Animales , Bloqueadores de los Canales de Calcio/farmacología , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/fisiología , Ácido Glutámico/metabolismo , Masculino , Ratas , Ratas Wistar , Sustancia Negra/citología , Sustancia Negra/fisiología , Subtálamo/citología , Subtálamo/fisiología
9.
Synapse ; 74(3): e22139, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31610050

RESUMEN

CB2 receptors (CB2 R) are expressed in midbrain neurons. To evidence the control of dopamine release in dorsal striatum by CB2 R, we performed experiments of [3 H]-dopamine release in dorsal striatal slices. We found a paradoxical increase in K+ -induced [3 H]-dopamine release by CB2 R activation with GW 833972A and JWH 133 two selective agonist. To understand the mechanism involved, we tested for a role of the D2 autoreceptor in this effect; because in pallidal structures, the inhibitory effect of CB1 receptors (CB1 R) on GABA release is switched to a stimulatory effect by D2 receptors (D2 R). We found that the blockade of D2 autoreceptors with sulpiride prevented the stimulatory effect of CB2 R activation; in fact, under this condition, CB2 R decreased dopamine release, indicating the role of the D2 autoreceptor in the paradoxical increase. We also found that the effect occurs in nigrostriatal terminals, since lesions with 6-OH dopamine in the middle forebrain bundle prevented CB2 R effects on release. In addition, D2 -CB2 R interaction promoted cAMP accumulation, and the increase in [3 H]-dopamine release was prevented by PKA blockade. D2 -CB2 R coprecipitation and proximity ligation assay studies indicated a close interaction of receptors that could participate in the observed effects. Finally, intrastriatal injection of CB2 R agonist induced contralateral turning in amphetamine-treated rats, which was prevented by sulpiride, indicating the role of the interaction in motor behavior. Thus, these data indicate that the D2 autoreceptor switches, from inhibitory to stimulatory, the CB2 R effects on dopamine release, involving the cAMP â†’ PKA pathway in nigrostriatal terminals.


Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Receptor Cannabinoide CB2/metabolismo , Receptores de Dopamina D2/metabolismo , Sustancia Negra/metabolismo , Anfetamina/farmacología , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Células Cultivadas , Cuerpo Estriado/citología , Cuerpo Estriado/efectos de los fármacos , AMP Cíclico/metabolismo , Antagonistas de los Receptores de Dopamina D2/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Masculino , Movimiento , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/metabolismo , Terminales Presinápticos/fisiología , Piridinas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB2/agonistas , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sulpirida/farmacología
10.
Synapse ; 74(8): e22152, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32068305

RESUMEN

Dopamine D3 R are widely expressed in basal ganglia where interact with D1 R. D3 R potentiate cAMP accumulation and GABA release stimulated by D1 R in striatonigral neurons through "atypical" signaling. During dopaminergic denervation, D3 R signaling changes to a "typical" in which antagonizes the effects of D1 R, the mechanisms of this switching are unknown. D3 nf splice variant regulates membrane anchorage and function of D3 R and decreases in denervation; thus, it is possible that D3 R signaling switching correlates with changes in D3 nf expression and increases of membranal D3 R that mask D3 R atypical effects. We performed experiments in unilaterally 6-hydroxydopamine lesioned rats and found a decrease in mRNA and protein of D3 nf, but not of D3 R in the denervated striatum. Proximity ligation assay showed that D3 R-D3 nf interaction decreased after denervation, whereas binding revealed an increased Bmax in D3 R. The new D3 R antagonized cAMP accumulation and GABA release stimulated by D1 R; however, in the presence of N-Ethylmaleimide (NEM), to block Gi protein signaling, activation of D3 R produced its atypical signaling stimulating D1 R effects. Finally, we investigated if the typical and atypical effects of D3 R modulating GABA release are capable of influencing motor behavior. Injections of D3 R agonist into denervated nigra decreased D1 R agonist-induced turning behavior but potentiated it in the presence of NEM. Our data indicate the coexistence of D3 R typical and atypical signaling in striatonigral neurons during denervation that correlated with changes in the ratio of expression of D3 nf and D3 R isoforms. The coexistence of both atypical and typical signaling during denervation influences motor behavior.


Asunto(s)
Receptores de Dopamina D3/metabolismo , Transducción de Señal , Sustancia Negra/metabolismo , Animales , AMP Cíclico/metabolismo , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/fisiología , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Masculino , Movimiento , Bloqueo Nervioso , Empalme del ARN , Ratas , Ratas Wistar , Receptores de Dopamina D3/genética , Sustancia Negra/citología , Sustancia Negra/fisiología , Ácido gamma-Aminobutírico/metabolismo
11.
Cell Mol Biol (Noisy-le-grand) ; 66(4): 191-198, 2020 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-32583795

RESUMEN

Human skin possesses an essential function in the maintenance of individuals' health. However, it may undergo a variety of lesions that produce wounds of distinct severity. In this respect, instantly after any skin wound, the process of tissue regeneration and repair initiates. Nevertheless, diverse factors can delay this process, including bacterial infections, nutritional status, age, hypoxia, chronic diseases, necrosis, and vascular and arterial diseases. Thus, wound dressings are frequently used to improve wound healing. Those wound dressings are fabricated with diverse materials, which confer them different properties. In this regard, hyaluronic acid is a natural polysaccharide widely distributed in extracellular matrices of mammal tissues, which possesses remarkable attributes in terms of biocompatibility, biodegradability, and low cost. Moreover, hyaluronic acid exhibits several beneficial effects on wound healing, such as the decrease of inflammatory processes, regulation of tissue remodeling, and enhancement of angiogenesis. Therefore, in recent years, there is growing attention in this polysaccharide for the design and manufacture of novel wound dressings, which have shown encouraging properties. Here, we describe the different approaches of hyaluronic acid for the production of wound dressings, encompassing hydrogels, films, scaffolds, foams, topical formulations, and nanoformulations, as well as its beneficial effects on wound healing. Finally, we discuss perspectives about the use of hyaluronic acid in wound dressings.


Asunto(s)
Vendajes , Ácido Hialurónico/uso terapéutico , Heridas y Lesiones/terapia , Animales , Preparaciones de Acción Retardada/farmacología , Humanos , Ácido Hialurónico/química , Andamios del Tejido/química , Cicatrización de Heridas/efectos de los fármacos
12.
Cell Mol Biol (Noisy-le-grand) ; 66(4): 199-207, 2020 Jun 25.
Artículo en Inglés | MEDLINE | ID: mdl-32583796

RESUMEN

Controlled release is of vital relevance for many drugs; thus, there is a keen interest in materials that can improve the release profiles of formulations administered via buccal, transdermal, ophthalmic, vaginal, and nasal. The desirable effects of those materials include the improvement of stability, adhesiveness, solubility, and retention time. Hence, different synthetic and natural polymers are utilized to achieve these objectives. In this respect, xanthan gum is an anionic polysaccharide that can be obtained from Xanthomonas bacteria. It is a natural polymer broadly employed in numerous food products, lotions, shampoos, and dermatological articles. Furthermore, due to its physicochemical features, xanthan gum is growingly utilized for the development and improvement of drug delivery systems. In this regard, encouraging findings have been revealed by recent formulations for pharmaceutical applications, including antiviral carriers, antibacterial transporters, transdermal patches, vaginal formulations, and anticancer medications. In this article, we perform a concise description of the chemical properties of xanthan gum and its role as a modifier of drug release. Furthermore, we present an outlook of the state of the art of research focused on the utilization of xanthan gum in varied pharmaceutical formulations, which include tablets, films, hydrogels, and nanoformulations. Finally, we discuss some perspectives about the use of xanthan gum in these formulations.


Asunto(s)
Liberación de Fármacos , Polisacáridos Bacterianos/química , Animales , Preparaciones de Acción Retardada , Formas de Dosificación , Humanos , Hidrogeles/química , Nanopartículas/química
13.
J Pharm Pharm Sci ; 23: 314-332, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33751927

RESUMEN

Elastin is one of the main components of the extracellular matrix; it provides resistance and elasticity to a variety of tissues and organs of the human body, besides participating in cellular signaling. On the other hand, elastin-derived peptides are synthetic biopolymers with a similar conformation and structure to elastin, but these possess the advantage of solubility in aqueous mediums. Due to their biological activities and physicochemical properties, elastin and related peptides may be applied as biomaterials to develop diverse biomedical devices, including scaffolds, hydrogels, and drug delivery systems for tissue engineering. Likewise, the combination of elastin with natural or synthetic polymers has demonstrated to improve the mechanical properties of biomedical products and drug delivery systems. Here we comprehensively describe the physicochemical properties and physiological functions of elastin. Moreover, we offer an overview of the use of elastin and its derivative polymers as biomaterials to develop scaffolds and hydrogels for tissue engineering. Finally, we discuss some perspectives on the employment of these biopolymers to fabricate new biomedical products.


Asunto(s)
Materiales Biocompatibles/química , Elastina/química , Sistemas de Liberación de Medicamentos , Humanos , Hidrogeles/síntesis química , Hidrogeles/química , Péptidos/química , Ingeniería de Tejidos
14.
Synapse ; 72(11): e22061, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30022523

RESUMEN

Recent studies suggested the expression of CB2 receptors in neurons of the CNS, however, most of these studies have only explored one aspect of the receptors, i.e., expression of protein, messenger RNA, or functional response, and more complete studies appear to be needed to establish adequately their role in the neuronal function. Electron microscopy studies showed the presence of CB2r in asymmetric terminals of the substantia nigra pars reticulata (SNr), and its mRNA appeared is expressed in the subthalamic nucleus. Here, we explore the expression, source, and functional effects of such receptors by different experimental approaches. Through PCR and immunochemistry, we showed mRNA and protein for CB2rs in slices and primary neuronal cultures from subthalamus. GW833972A, GW405833, and JHW 133, three CB2r agonists dose-dependent inhibited K+ -induced [3 H]-Glutamate release in slices of SNr, and the two antagonist/inverse agonists, JTE-907 and AM630, but not AM281, a CB1r antagonist, prevented GW833972A effect. Subthalamus lesions with kainic acid prevented GW833972A inhibition on release and decreased CB2r protein in nigral synaptosomes, thus nigral CB2rs originate in subthalamus. Inhibition of [3 H]-Glutamate release was PTX- and gallein-sensitive, suggesting a Gißγ -mediated effect. P/Q Ca2+ -type channel blocker, ω-Agatoxin-TK, also inhibited the [3 H]-Glutamate release, this effect was occluded with GW833972A inhibition, indicating that the ßγ subunit effect is exerted on Ca2+ channel activity. Finally, microinjections of GW833972A in SNr induced contralateral turning. Our data showed that presynaptic CB2rs inhibit [3 H]-Glutamate release in subthalamo-nigral terminals by P/Q-channels modulation through the Gißγ subunit and suggested their participation in motor behavior.


Asunto(s)
Cuerpo Estriado/metabolismo , Ácido Glutámico/metabolismo , Terminales Presinápticos/metabolismo , Receptor Cannabinoide CB2/metabolismo , Sustancia Negra/metabolismo , Animales , Canales de Calcio/metabolismo , Células Cultivadas , Cuerpo Estriado/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neurotransmisores/farmacología , Terminales Presinápticos/efectos de los fármacos , Cultivo Primario de Células , ARN Mensajero/metabolismo , Ratas Wistar , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/antagonistas & inhibidores , Sustancia Negra/efectos de los fármacos , Núcleo Subtalámico/efectos de los fármacos , Núcleo Subtalámico/metabolismo , Técnicas de Cultivo de Tejidos , Tritio
15.
Synapse ; 72(8): e22036, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29740871

RESUMEN

Aging is a stage of life where cognitive and motor functions are impaired. This is because oxidative and inflammatory processes exacerbate neurodegeneration, which affects dendritic morphology and neuronal communication of limbic regions with memory loss. Recently, the use of trophic substances has been proposed to prevent neuronal deterioration. The neuropeptide-12 (N-PEP-12) has been evaluated in elderly patients with dementia, showing improvements in cognitive tasks due to acts as a neurotrophic factor. In the present work, we evaluated the effect of N-PEP-12 on motor activity and recognition memory, as well as its effects on dendritic morphology and the immunoreactivity of GFAP, Synaptophysin (SYP), and BDNF in neurons of the prefrontal cortex (PFC), dorsal hippocampus (DH) and nucleus accumbens (NAcc) of aged rats. The results show that N-PEP-12 improved the recognition memory, but the motor activity was not modified compared to the control animals. N-PEP-12 increases the density of dendritic spines and the total dendritic length in neurons of the PFC (layers 3 and 5) and in DH (CA1 and CA3). Interestingly NAcc neurons showed a reduction in the number of dendritic spines. In the N-PEP-12 animals, when evaluating the immunoreactivity for SYP and BDNF, there was an increase in the three brain regions, while the mark for GFAP decreased significantly. Our results suggest that N-PEP-12 promotes neuronal plasticity in the limbic system of aged animals, which contributes to improving recognition memory. In this sense, N-PEP-12 can be considered as a pharmacological alternative to prevent or delay brain aging and control senile dementias.


Asunto(s)
Envejecimiento/efectos de los fármacos , Aminoácidos/farmacología , Sistema Límbico/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Nootrópicos/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Envejecimiento/metabolismo , Envejecimiento/patología , Envejecimiento/psicología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Dendritas/efectos de los fármacos , Dendritas/metabolismo , Dendritas/patología , Proteína Ácida Fibrilar de la Glía/metabolismo , Sistema Límbico/metabolismo , Sistema Límbico/patología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Plasticidad Neuronal/fisiología , Ratas Sprague-Dawley , Reconocimiento en Psicología/fisiología , Sinaptofisina/metabolismo
16.
Synapse ; 71(3)2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27997735

RESUMEN

Curcuma is a natural compound that has shown neuroprotective properties, and has been reported to prevent aging and improve memory. While the mechanism(s) underlying these effects are unclear, they may be related to increases in neural plasticity. Morphological changes have been reported in neuronal dendrites in the limbic system in animals and elderly humans with cognitive impairment. In this regard, there is a need to use alternative therapies that delay the onset of morphologies and behavioral characteristics of aging. Therefore, the objective of this study was to evaluate the effect of curcuma on cognitive processes and dendritic morphology of neurons in the prefrontal cortex (PFC), the CA1 and CA3 regions of the dorsal hippocampus, the dentate gyrus, and the basolateral amygdala (BLA) of aged rats. 18-month-old rats were administered curcuma (100 mg/kg) daily for 60 days. After treatment, recognition memory was assessed using the novel object recognition test. Curcuma-treated rats showed a significant increase in the exploration quotient. Dendritic morphology was assessed by Golgi-Cox staining and followed by Sholl analysis. Curcuma-treated rats showed a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC, the CA1 and CA3, and the BLA. The preservation of dendritic morphology was positively correlated with cognitive improvements. Our results suggest that curcuma induces modification of dendritic morphology in the aforementioned regions. These changes may explain how curcuma slows the aging process that has already begun in these animals, preventing deterioration in neuronal morphology of the limbic system and recognition memory.


Asunto(s)
Envejecimiento , Trastornos del Conocimiento , Dendritas/efectos de los fármacos , Sistema Límbico/efectos de los fármacos , Extractos Vegetales/farmacología , Animales , Conducta Animal/efectos de los fármacos , Curcuma , Sistema Límbico/patología , Masculino , Ratas , Ratas Sprague-Dawley
17.
Synapse ; 70(5): 206-17, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26789275

RESUMEN

Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimer's disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1- and CA3-dorsal hippocampus (DH) as well as CA1-ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18-month-old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi-Cox stain procedure, followed by Sholl analysis on 20-month-old rats. In all resveratrol-treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimer's disease.


Asunto(s)
Antioxidantes/farmacología , Dendritas/efectos de los fármacos , Hipocampo/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Estilbenos/farmacología , Animales , Antioxidantes/administración & dosificación , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Masculino , Corteza Prefrontal/citología , Corteza Prefrontal/crecimiento & desarrollo , Células Piramidales/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Resveratrol , Estilbenos/administración & dosificación
18.
Neurobiol Dis ; 74: 336-46, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25517101

RESUMEN

In striatonigral projections activation of dopamine D3 receptors (D3Rs) potentiates the stimulation of GABA release and cAMP production caused by activation of dopamine D1 receptors (D1Rs). Cytoplasmic [Ca(2+)] in the terminals controls this response by modulating CaMKII, an enzyme that depresses D3R action. To examine the effects of dopamine deprivation on D3R signaling we investigated their function in striatonigral terminals of hemiparkinsonian rats. Denervation switched the signaling cascade initiated by D3R activation. In the non-lesioned side activation of D3R potentiated the stimulatory effects of D1R activation on cAMP production and K(+)-depolarization induced [(3)H] GABA release. In contrast, in the denervated side the stimulatory effects of both D1R activation and forskolin administration were blocked by D3R activation. In non-lesioned slices, D3R responses were inhibited by the activation of CaMKII produced by K(+)-depolarization (via increased Ca(2+) entry). The CaMKII-induced inhibition was blocked by the selective inhibitor KN-62. In denervated tissues the response to D3R stimulation was not modified either by K(+) depolarization or by blocking CaMKII with KN-62. Immunoblotting studies showed that depolarization-induced CaMKII binding to the D3 receptor and CaMKII phosphorylation were suppressed in denervated tissues. We also determined calmodulin expression with PCR and immunoblot techniques. Both techniques showed that calmodulin expression was depressed in the lesioned side. In sum, our studies show that dopaminergic denervation switches the D3R signaling cascade and depresses CaMKII signaling through a process that appears to involve reduced calmodulin levels. Since calmodulin is a major cytoplasmic Ca(2+) buffer our findings suggest that abnormal Ca(2+) buffering may be an important component of the abnormalities observed during dopaminergic denervation.


Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Calmodulina/metabolismo , Cuerpo Estriado/metabolismo , Neuronas Dopaminérgicas/metabolismo , Receptores de Dopamina D3/metabolismo , Sustancia Negra/metabolismo , Animales , Calcio/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/antagonistas & inhibidores , Cuerpo Estriado/efectos de los fármacos , AMP Cíclico/metabolismo , Fosfatos de Dinucleósidos/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Masculino , Haz Prosencefálico Medial/fisiopatología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Oxidopamina , Fosforilación/efectos de los fármacos , Ratas Wistar , Transducción de Señal , Sustancia Negra/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Ácido gamma-Aminobutírico/metabolismo
19.
Synapse ; 69(3): 103-14, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25522178

RESUMEN

The cannabinoid CB1 (CB1R) and dopaminergic D2 (D2R) receptors modify GABAergic transmission in the globus pallidus. Although dopaminergic denervation produces changes in the expression and supersensitization of these receptors, the consequences of these changes on GABAergic neurotransmission are unknown. The aim of this study was to show the effects of CB1R and D2R activation and coactivation on the uptake and release of [(3) H]GABA in the globus pallidus of hemiparkinsonian rats as well as their effects on motor behavior. The activation of CB1R blocked GABA uptake and decreased GABA release in the globus pallidus in the dopamine denervated side, whereas the co-activation of CB1R-D2R increased GABA release and had no effect on GABA uptake. A microinjection of the CB1R agonist ACEA into the globus pallidus ipsilaterally to a 6-OHDA lesion potentiated turning behavior that was induced by methamphetamine. However, a microinjection of the D2R agonist quinpirole did not modify this behavior, and a microinjection of a mixture of CB1R and D2R agonists significantly potentiated turning behavior. The behavioral effects produced after the activation of the CB1R and the co-activation of CB1R and D2R can be explained by increased GABAergic neurotransmission produced by a block of GABA uptake and an increase in the release of GABA in the globus pallidus, respectively.


Asunto(s)
Neuronas GABAérgicas/metabolismo , Globo Pálido/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptores de Dopamina D2/metabolismo , Transmisión Sináptica , Animales , Ácidos Araquidónicos/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Globo Pálido/efectos de los fármacos , Globo Pálido/fisiología , Masculino , Metanfetamina/farmacología , Movimiento , Oxidopamina/toxicidad , Quinpirol/farmacología , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/agonistas , Receptores de Dopamina D2/agonistas , Ácido gamma-Aminobutírico/metabolismo
20.
Carbohydr Polym ; 336: 122121, 2024 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-38670753

RESUMEN

This study aimed to modify chitosan (CS) by gamma irradiation and use it as a surface coating of nanoparticles (NPs) fabricated of poly lactic-co-glycolic acid (PLGA) to create mostly biocompatible nanosystems that can transport drugs to neurons. Gamma irradiation produced irradiated CS (CSγ) with a very low molecular weight (15.2-19.2 kDa). Coating NPs-PLGA with CSγ caused significant changes in their Z potential, making it slightly positive (from -21.7 ± 2.8 mV to +7.1 ± 2.3 mV) and in their particle size (184.4 0.4 ± 7.9 nm to 211.9 ± 14.04 nm). However, these changes were more pronounced in NPs coated with non-irradiated CS (Z potential = +54.0 ± 1.43 mV, size = 348.1 ± 16.44 nm). NPs coated with CSγ presented lower cytotoxicity and similar internalization levels in SH-SY5Y neuronal cells than NPs coated with non-irradiated CS, suggesting higher biocompatibility. Highly biocompatible NPs are desirable as nanocarriers to deliver drugs to the brain, as they help maintain the structure and function of the blood-brain barrier. Therefore, the NPs developed in this study could be evaluated as drug-delivery systems for treating brain diseases.


Asunto(s)
Quitosano , Nanopartículas , Neuronas , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Quitosano/química , Humanos , Nanopartículas/química , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Portadores de Fármacos/química , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Tamaño de la Partícula , Rayos gamma
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