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1.
Cell Transplant ; 32: 9636897231158967, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36919673

RESUMEN

The field of stem cell therapy is growing rapidly and hopes to offer an alternative solution to diseases that are historically treated medically or surgically. One such focus of research is the treatment of medically refractory epilepsy, which is traditionally approached from a surgical or interventional standpoint. Research shows that stem cell transplantation has potential to offer significant benefits to the epilepsy patient by reducing seizure frequency, intensity, and neurological deficits that often result from the condition. This review explores the basic science progress made on the topic of stem cells and epilepsy by focusing on experiments using animal models and highlighting the most recent developments from the last 4 years.


Asunto(s)
Epilepsia , Trasplante de Células Madre , Células Madre , Epilepsia/cirugía , Epilepsia/terapia , Convulsiones/terapia
2.
Pharmacol Res Perspect ; 10(3): e00947, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35599337

RESUMEN

The prolonged exposure to obesogenic diets disrupts the mesocortical dopaminergic input to the prefrontal cortex (PFC). This leads to suboptimal dopamine levels in this brain region, which affects cognition and control of food intake. Treatments that restore mesocortical dopaminergic neurotransmission may improve obesity-associated cognitive dysfunction and modulate food intake to induce weight loss. Given the complexity and multifactorial nature of obesity, combination treatments would likely achieve sizeable and sustained body weight loss and improve obesity-linked outcomes, such as cognitive dysfunction. Given this background, we hypothesize that concomitant activation of serotonin 5-HT2C and histamine H1 receptors, coupled with antagonism of histamine H3 receptors, synergistically modulates mesocortical dopamine neurotransmission and ameliorates obesity-induced cognitive dysfunction. We propose to test the hypothesis in a diet-induced obesity (DIO) rat model by treating animals with the 5-HT2C agonist lorcaserin and the H1 agonist and H3 antagonist betahistine. Consistent with our hypothesis, both lorcaserin and betahistine have been shown to reduce body weight in humans with obesity and animals. Both drugs have been demonstrated to improve cognitive functions by influencing dopaminergic signaling in the PFC. The proposed combination treatment addresses the paucity of studies on obesity treatments that improve cognitive function. This research may also help identify a potential targetable mechanism connecting obesity and neurocognitive outcomes.


Asunto(s)
Betahistina , Disfunción Cognitiva , Animales , Benzazepinas , Betahistina/farmacología , Betahistina/uso terapéutico , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Dopamina , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Ratas , Ratas Sprague-Dawley
3.
Transl Psychiatry ; 12(1): 83, 2022 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-35220393

RESUMEN

Childhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether exogenous NRG1 administration reduces hippocampal abnormalities and neuroinflammation in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): (1) control diet+vehicle (CDV); (2) CD + NRG1 (CDN) (daily intraperitoneal injections: 5 µg/kg/day; between postnatal day, PND 21-PND 41); (3) WD + VEH (WDV); (4) WD + NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-γ) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1α, TNF-α, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Although the results did not provide sufficient evidence to conclude that exogenous NRG1 administration is beneficial to alleviate obesity-related outcomes in adolescent rats, we identified a potential novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals.


Asunto(s)
Neurregulina-1 , Obesidad Infantil , Animales , Ansiedad , Dieta , Neurregulina-1/metabolismo , Neurregulina-1/farmacología , Enfermedades Neuroinflamatorias , Ratas , Ratas Endogámicas Lew
4.
Eur J Pharmacol ; 892: 173826, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33347825

RESUMEN

Finding alternative treatments for attention-deficit/hyperactivity disorder (ADHD) is crucial given the safety and efficacy problems of current ADHD medications. Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS), is a norepinephrine prodrug that enhances brain norepinephrine and dopamine levels. In this study, we used electrophysiological tests to examine effects of L-DOPS on the prefrontal cortex (PFC) and dopamine neurons in the ventral tegmental area. We also conducted behavioral tests to assess L-DOPS' effects on ADHD-like behaviors in rats. In chloral hydrate-anesthetized rats, PFC local field potentials oscillated between the active, depolarized UP state and the hyperpolarized DOWN state. Mimicking the effect of d-amphetamine, L-DOPS, given after the peripheral amino acid decarboxylase inhibitor, benserazide (BZ), increased the amount of time the PFC spent in the UP state, indicating an excitatory effect of L-DOPS on PFC neurons. Like d-amphetamine, L-DOPS also inhibited dopamine neurons, an effect significantly reversed by the D2-like receptor antagonist raclopride. In the behavioral tests, BZ + L-DOPS improved hyperactivity, inattention and impulsive action of the adolescent spontaneously hypertensive rat (SHR/NCrl), well-validated animal model of the combined type of ADHD. BZ + L-DOPS also reduced impulsive choice and impulsive action of Wistar rats, but did not ameliorate the inattentiveness of Wistar Kyoto rats (WKY/NCrl), proposed model of the ADHD-predominantly inattentive type. In conclusion, L-DOPS produced effects on the PFC and dopamine neurons characteristic of drugs used to treat ADHD. BZ + L-DOPS ameliorated ADHD-like behaviors in rats suggesting its potential as an alternative ADHD treatment.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Dopaminérgicos/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Droxidopa/farmacología , Corteza Prefrontal/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Atención/efectos de los fármacos , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Benserazida/farmacología , Descuento por Demora/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Quimioterapia Combinada , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Especificidad de la Especie , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiopatología
5.
Artículo en Inglés | MEDLINE | ID: mdl-30125623

RESUMEN

Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder characterized by varying levels of hyperactivity, inattention, and impulsivity. Patients with ADHD are often classified as (1) predominantly hyperactive-impulsive, (2) predominantly inattentive, and (3) combined type. There is a growing interest in developing specific animal models that would recapitulate specific clinical forms of ADHD, with the goal of developing specific therapeutic strategies. In our previous study, we have identified Ataxin-7 (Atxn7) as a hyperactivity-associated gene. Here, we generated Atxn7 overexpressing (Atxn7 OE) mice to investigate whether the increased Atxn7 expression in the brain correlates with ADHD-like behaviors. Quantitative real-time polymerase chain reaction and immunofluorescence confirmed overexpression of the Atxn7 gene and protein in the prefrontal cortex (PFC) and striatum (STR) of the Atxn7 OE mice. The Atxn7 OE mice displayed hyperactivity and impulsivity, but not inattention. Interestingly, treatment with the ADHD drug, atomoxetine (3 mg/kg, intraperitoneal), attenuated ADHD-like behaviors and reduced Atxn7 gene expression in the PFC and STR of these mice. These findings suggest that Atxn7 plays a role in the pathophysiology of ADHD, and that the Atxn7 OE mice can be used as an animal model of the hyperactive-impulsive phenotype of this disorder. Although confirmatory studies are warranted, the present study provides valuable information regarding the potential genetic underpinnings of ADHD.


Asunto(s)
Inhibidores de Captación Adrenérgica/uso terapéutico , Ataxina-7/metabolismo , Clorhidrato de Atomoxetina/uso terapéutico , Hipercinesia/tratamiento farmacológico , Hipercinesia/genética , Conducta Impulsiva/efectos de los fármacos , Animales , Ataxina-7/genética , Descuento por Demora/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Conducta Impulsiva/fisiología , Locomoción/efectos de los fármacos , Locomoción/genética , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , ARN Mensajero , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Estadísticas no Paramétricas
6.
Brain Circ ; 4(3): 99-108, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30450415

RESUMEN

Tissue plasminogen activator (tPA) thrombolysis continues to be the gold standard therapy for ischemic stroke. Due to the time-limited treatment window, within 4.5 h of stroke onset, and a variety of potentially deadly complications related to delayed administration, particularly hemorrhagic transformation (HT), clinical use of tPA is limited. Combination therapies with other interventions, drug or nondrug, have been hypothesized as a logical approach to enhancing tPA effectiveness. Here, we discuss various potential pharmacological and nondrug treatments to minimize adverse effects, primarily HT, associated with delayed tPA administration. Pharmacological interventions include many that support the integrity of the blood-brain barrier (i.e., atorvastatin, batimastat, candesartan, cilostazol, fasudil, and minocycline), promote vascularization and preserve cerebrovasculature (i.e., coumarin derivative IMM-H004 and granulocyte-colony stimulating factor), employing other mechanisms of action (i.e., oxygen transporters and ascorbic acid). Nondrug treatments are comprised of stem cell transplantation and gas therapies with multi-faceted approaches. Combination therapy with tPA and the aforementioned treatments demonstrated promise for mitigating the adverse complications associated with delayed tPA treatment and rescuing stroke-induced behavioral deficits. Therefore, the conjunctive therapy method is a novel therapeutic approach that can attempt to minimize the limitations of tPA treatment and possibly increase the therapeutic window for ischemic stroke treatment.

7.
Int J Mol Sci ; 19(6)2018 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-29857523

RESUMEN

When given beyond 4.5 h of stroke onset, tissue plasminogen activator (tPA) induces deleterious side effects in the ischemic brain, notably, hemorrhagic transformation (HT). We examined the efficacy of granulocyte-colony stimulating factor (G-CSF) in reducing delayed tPA-induced HT, cerebral infarction, and neurological deficits in a thromboembolic (TE) stroke model, and whether the effects of G-CSF were sustained for longer periods of recovery. After stroke induction, rats were given intravenous saline (control), tPA (10 mg/kg), or G-CSF (300 µg/kg) + tPA 6 h after stroke. We found that G-CSF reduced delayed tPA-associated HT by 47%, decreased infarct volumes by 33%, and improved motor and neurological deficits by 15% and 25%, respectively. It also prevented delayed tPA treatment-induced mortality by 46%. Immunohistochemistry showed 1.5- and 1.8-fold enrichment of the endothelial progenitor cell (EPC) markers CD34+ and VEGFR2 in the ischemic cortex and striatum, respectively, and 1.7- and 2.8-fold increases in the expression of the vasculogenesis marker von Willebrand factor (vWF) in the ischemic cortex and striatum, respectively, in G-CSF-treated rats compared with tPA-treated animals. Flow cytometry revealed increased mobilization of CD34+ cells in the peripheral blood of rats given G-CSF. These results corroborate the efficacy of G-CSF in enhancing the therapeutic time window of tPA for stroke treatment via EPC mobilization and enhancement of vasculogenesis.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/farmacología , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/etiología , Activador de Tejido Plasminógeno/farmacología , Animales , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Encéfalo/patología , Infarto Cerebral/tratamiento farmacológico , Infarto Cerebral/etiología , Infarto Cerebral/prevención & control , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Quimioterapia Combinada , Expresión Génica , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Hemorragia/tratamiento farmacológico , Hemorragia/etiología , Hemorragia/prevención & control , Inmunohistoquímica , Masculino , Mortalidad , Ratas , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/mortalidad , Factores de Tiempo , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Tejido Plasminógeno/efectos adversos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo
8.
Neuropharmacology ; 131: 431-439, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29339293

RESUMEN

Amphetamine-like psychostimulants, including methylphenidate, have been shown to produce two opposing effects on dopamine (DA) neurons: a DA receptor-mediated feedback inhibition and a non-DA receptor-mediated excitation. To test whether the latter effect is mediated through the prefrontal cortex (PFC), we made dual-site recordings from the PFC and ventral tegmental area (VTA). Consistent with previous reports, methylphenidate inhibited VTA DA neurons. The D2 receptor antagonist raclopride completely reversed the inhibition and further increased the activity, particularly bursting, to above pre-drug baseline. This increase in DA cell activity was blocked by the α1 receptor antagonist prazosin, suggesting an effect mediated through α1 receptors. Recordings in the PFC showed that methylphenidate increased PFC UP state duration and shifted the functional coupling between the PFC and DA neurons from negative to positive. The former effect was partially reversed by not only prazosin, but also raclopride, whereas the latter was reversed only by raclopride. These results suggest that methylphenidate increases PFC cell activity through both α1 and D2 receptors. Its effect on PFC-DA cell functional coupling, however, is mediated through D2 receptors. The finding that the latter effect was unaffected by prazosin further suggests that it does not play a significant role in the α1-mediated excitatory effect of methylphenidate on DA neurons. However, the shift in PFC-DA cell functional coupling from negative to positive may significantly alter the relative timing between DA and glutamate release from DA and PFC terminals and thus the synaptic plasticity that depends on DA-glutamate interaction.


Asunto(s)
Inhibidores de Captación de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Metilfenidato/farmacología , Corteza Prefrontal/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Neuronas Dopaminérgicas/fisiología , Relación Dosis-Respuesta a Droga , Masculino , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiología , Corteza Prefrontal/fisiología , Ratas Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Área Tegmental Ventral/fisiología
9.
Int J Mol Sci ; 18(12)2017 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-29257093

RESUMEN

Tissue plasminogen activator (tPA) thrombolysis remains the gold standard treatment for ischemic stroke. A time-constrained therapeutic window, with the drug to be given within 4.5 h after stroke onset, and lethal side effects associated with delayed treatment, most notably hemorrhagic transformation (HT), limit the clinical use of tPA. Co-administering tPA with other agents, including drug or non-drug interventions, has been proposed as a practical strategy to address the limitations of tPA. Here, we discuss the pharmacological and non-drug approaches that were examined to mitigate the complications-especially HT-associated with delayed tPA treatment. The pharmacological treatments include those that preserve the blood-brain barrier (e.g., atovarstatin, batimastat, candesartan, cilostazol, fasudil, minocycline, etc.), enhance vascularization and protect the cerebrovasculature (e.g., coumarin derivate IMM-H004 and granulocyte-colony stimulating factor (G-CSF)), and exert their effects through other modes of action (e.g., oxygen transporters, ascorbic acid, etc.). The non-drug approaches include stem cell treatments and gas therapy with multi-pronged biological effects. Co-administering tPA with the abovementioned therapies showed promise in attenuating delayed tPA-induced side effects and stroke-induced neurological and behavioral deficits. Thus, adjunctive treatment approach is an innovative therapeutic modality that can address the limitations of tPA treatment and potentially expand the time window for ischemic stroke therapy.


Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Accidente Cerebrovascular/tratamiento farmacológico , Terapia Trombolítica/métodos , Animales , Isquemia Encefálica/terapia , Quimioterapia Adyuvante , Fibrinolíticos/administración & dosificación , Fibrinolíticos/efectos adversos , Fibrinolíticos/uso terapéutico , Humanos , Trasplante de Células Madre/métodos , Accidente Cerebrovascular/terapia
10.
Behav Genet ; 47(5): 564-580, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28744604

RESUMEN

Impulsivity, the predisposition to act prematurely without foresight, is associated with a number of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). Identifying genetic underpinnings of impulsive behavior may help decipher the complex etiology and neurobiological factors of disorders marked by impulsivity. To identify potential genetic factors of impulsivity, we examined common differentially expressed genes (DEGs) in the prefrontal cortex (PFC) of adolescent SHR/NCrl and Wistar rats, which showed marked decrease in preference for the large but delayed reward, compared with WKY/NCrl rats, in the delay discounting task. Of these DEGs, we examined drug-responsive transcripts whose mRNA levels were altered following treatment (in SHR/NCrl and Wistar rats) with drugs that alleviate impulsivity, namely, the ADHD medications methylphenidate and atomoxetine. Prefrontal cortical genetic overlaps between SHR/NCrl and Wistar rats in comparison with WKY/NCrl included genes associated with transcription (e.g., Btg2, Fos, Nr4a2), synaptic plasticity (e.g., Arc, Homer2), and neuron apoptosis (Grik2, Nmnat1). Treatment with methylphenidate and/or atomoxetine increased choice of the large, delayed reward in SHR/NCrl and Wistar rats and changed, in varying degrees, mRNA levels of Nr4a2, Btg2, and Homer2, genes with previously described roles in neuropsychiatric disorders characterized by impulsivity. While further studies are required, we dissected potential genetic factors that may influence impulsivity by identifying genetic overlaps in the PFC of "impulsive" SHR/NCrl and Wistar rats. Notably, these are also drug-responsive transcripts which may be studied further as biomarkers to predict response to ADHD drugs, and as potential targets for the development of treatments to improve impulsivity.


Asunto(s)
Conducta Impulsiva/efectos de los fármacos , Conducta Impulsiva/fisiología , Corteza Prefrontal/efectos de los fármacos , Animales , Clorhidrato de Atomoxetina/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/genética , Conducta de Elección , Modelos Animales de Enfermedad , Masculino , Metilfenidato/metabolismo , Corteza Prefrontal/metabolismo , Ratas , Ratas Endogámicas SHR/genética , Ratas Endogámicas SHR/metabolismo , Ratas Endogámicas WKY/genética , Ratas Endogámicas WKY/metabolismo , Ratas Wistar/genética , Ratas Wistar/metabolismo
11.
Brain Circ ; 3(3): 143-151, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-30276316

RESUMEN

Traumatic brain injury (TBI) is now characterized as a progressive, degenerative disease and continues to stand as a prevalent cause of death and disability. The pathophysiology of TBI is complex, with a variety of secondary cell death pathways occurring which may persist chronically following the initial cerebral insult. Current therapeutic options for TBI are minimal, with surgical intervention or rehabilitation therapy existing as the only viable treatments. Considering the success of stem-cell therapies in various other neurological diseases, their use has been proposed as a potential potent therapy for patients suffering TBI. Moreover, stem cells are highly amenable to adjunctive use with other therapies, providing an opportunity to overcome the inherent limitations of using a single therapeutic agent. Our research has verified this additive potential by demonstrating the efficacy of co-delivering human umbilical cord blood (hUCB) cells with granulocyte-colony stimulating factor (G-CSF) in a murine model of TBI, providing encouraging results which support the potential of this approach to treat patients suffering from TBI. These findings justify ongoing research toward uncovering the mechanisms which underlie the functional improvements exhibited by hUCB + G-CSF combination therapy, thereby facilitating its safe and effect transition into the clinic. This paper is a review article. Referred literature in this paper has been listed in the reference section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.

12.
Neural Plast ; 2016: 1320423, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26966583

RESUMEN

Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a "safer" approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Terapias Complementarias/efectos adversos , Terapias Complementarias/métodos , Fitoterapia/efectos adversos , Fitoterapia/métodos , Ensayos Clínicos como Asunto , Quimioterapia Combinada , Humanos , Resultado del Tratamiento
13.
Eur J Pharmacol ; 764: 562-570, 2015 Oct 05.
Artículo en Inglés | MEDLINE | ID: mdl-26209364

RESUMEN

The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs.


Asunto(s)
Anfetamina/farmacología , Encéfalo/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/efectos de los fármacos , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Potenciales de Acción , Neuronas Adrenérgicas/efectos de los fármacos , Neuronas Adrenérgicas/metabolismo , Anfetamina/metabolismo , Animales , Encéfalo/metabolismo , Estimulantes del Sistema Nervioso Central/metabolismo , Cocaína/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Neuronas Dopaminérgicas/metabolismo , Humanos , Cinética , Plasticidad Neuronal , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo
14.
Neuropharmacology ; 99: 9-14, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26116818

RESUMEN

Adolescence is a period of enhanced vulnerability to the motivational properties of tobacco/cigarette smoking. Several studies have suggested that smoking initiation during this period will more likely lead to long-lasting cigarette or nicotine addiction. In the present study, we investigated the influences of adolescent cigarette smoke or nicotine exposure on the rewarding effects of nicotine, particularly whether these influences persist even after a long period of abstinence. Towards this, adolescent and adult Sprague-Dawley rats were repeatedly exposed to cigarette smoke or nicotine, for 14 days, and then were subjected to a 1-month abstinence period. Thereafter, the rewarding effects of nicotine were evaluated through the conditioned place preference (CPP) and self-administration (SA) tests. Even after a 1-month abstinence period, rats pre-exposed to either nicotine or cigarette smoke demonstrated enhanced CPP for the higher dose (0.6 mg/kg) of nicotine. Notably, cigarette smoke-preexposed adolescent rats, now adults, showed CPP for both 0.2 and 0.6 mg/kg dose of nicotine. Moreover, only these rats (pre-exposed to cigarette smoke during adolescence) showed significant acquisition and maintenance of nicotine (0.03 mg/kg/infusion) SA. These results suggest that cigarette smoke exposure during adolescence enhances sensitivity to the rewarding effects of nicotine in adulthood, even after a long period of abstinence. This may be a factor in the high rates of nicotine addiction and dependence observed in smokers who started during adolescence. More importantly, our findings highlight the enduring consequences of adolescent-onset cigarette smoking and the need to protect this vulnerable population.


Asunto(s)
Envejecimiento/efectos de los fármacos , Nicotina/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Recompensa , Contaminación por Humo de Tabaco/efectos adversos , Envejecimiento/psicología , Animales , Condicionamiento Psicológico/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Motivación , Ratas Sprague-Dawley , Autoadministración , Conducta Espacial/efectos de los fármacos , Tabaquismo/etiología , Tabaquismo/psicología
15.
Behav Brain Res ; 291: 268-276, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26048425

RESUMEN

Factor analyses of attention-deficit/hyperactivity (ADHD) symptoms divide the behavioral symptoms of ADHD into two separate domains, one reflecting inattention and the other, a combination of hyperactivity and impulsivity. Identifying domain-specific genetic risk variants may aid in the discovery of specific biological risk factors for ADHD. In contrast with data available on genes involved in hyperactivity and impulsivity, there is limited information on the genetic influences of inattention. Transcriptional profiling analysis in animal models of disorders may provide an important tool to identify genetic involvement in behavioral phenotypes. To explore some of the potential genetic underpinnings of ADHD inattention, we examined common differentially expressed genes (DEGs) in the prefrontal cortex of SHR/NCrl, the most validated animal model of ADHD and WKY/NCrl, animal model of ADHD-inattentive type. In contrast with Wistar rats, strain representing the "normal" heterogeneous population, SHR/NCrl and WKY/NCrl showed inattention behavior in the Y-maze task. The common DEGs in the PFC of SHR/NCrl and WKY/NCrl vs. Wistar rats are those involved in transcription (e.g. Creg1, Thrsp, Zeb2), synaptic transmission (e.g. Atp2b2, Syt12, Chrna5), neurological system process (e.g. Atg7, Cacnb4, Grin3a), and immune response (e.g. Atg7, Ip6k2, Mx2). qRT-PCR analyses validated expression patterns of genes representing the major functional gene families among the DEGs (Grin3a, Thrsp, Vof-16 and Zeb2). Although further studies are warranted, the present findings indicate novel genes associated with known functional pathways of relevance to ADHD which are assumed to play important roles in the etiology of ADHD-inattentive subtype.


Asunto(s)
Atención/fisiología , Aprendizaje por Laberinto/fisiología , Corteza Prefrontal/metabolismo , Animales , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Modelos Animales de Enfermedad , Expresión Génica , Perfilación de la Expresión Génica , Masculino , Pruebas Neuropsicológicas , Corteza Prefrontal/crecimiento & desarrollo , Análisis por Matrices de Proteínas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Especificidad de la Especie
16.
J Cereb Blood Flow Metab ; 35(2): 338-46, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25425079

RESUMEN

Treatment with tissue plasminogen activator (tPA) beyond the therapeutic time window (>4.5 hours post stroke) may produce hemorrhagic transformation (HT). Strategies that could extend the narrow time window of tPA will benefit a significant number of stroke patients. Male Sprague-Dawley rats underwent middle cerebral artery occlusion (MCAo) and given vehicle, tPA (10 mg/kg), or tPA and granulocyte colony-stimulating factor (G-CSF, 300 µg/kg), at 6 hours after MCAo. Twenty-four hours post treatment, G-CSF+tPA-treated stroke rats displayed 25% improvement in neurological functions and 38.9% reduction of hemorrhage, with Western blots showing 1.9- and 1.2-fold increments in Ang-2 expression in the ischemic cortex and striatum, respectively, and 3-fold increase in phosphorylated endothelial nitric oxide synthase expression in the ipsilateral cortex relative to tPA-treated rats. Immunohistochemistry also showed 2- and 2.8-fold increase in von-Willebrand expression, 3.2- and 2.2-fold increased CD34+ expression, and 4- and 13-fold upregulation of VEGFR-2 expression in the ischemic cortex and striatum, respectively, in G-CSF+tPA-treated stroke rats relative to tPA-treated subjects. Altogether, these findings indicate that G-CSF attenuated delayed tPA-induced HT likely via the enhancement of angiogenesis and vasculogenesis. The use of G-CSF to protect the vasculature may improve the clinical outcome of tPA even outside the currently indicated therapeutic window for ischemic stroke.


Asunto(s)
Isquemia Encefálica , Hemorragias Intracraneales , Neovascularización Fisiológica/efectos de los fármacos , Accidente Cerebrovascular , Activador de Tejido Plasminógeno/efectos adversos , Animales , Antígenos CD34/biosíntesis , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Regulación de la Expresión Génica/efectos de los fármacos , Hemorragias Intracraneales/inducido químicamente , Hemorragias Intracraneales/tratamiento farmacológico , Hemorragias Intracraneales/patología , Masculino , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/patología , Activador de Tejido Plasminógeno/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/biosíntesis , Factor de von Willebrand/biosíntesis
17.
Arch Pharm Res ; 38(5): 865-75, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25163681

RESUMEN

Attention-deficit/hyperactivity disorder (ADHD), the most commonly diagnosed neurobehavioral disorder of childhood, is usually treated with psychostimulants (e.g., amphetamine). Little is known about the neuronal and behavioral consequences of chronic amphetamine use or abuse in individuals with ADHD. Of all ADHD animal models, the spontaneously hypertensive rat (SHR) is the most validated and widely used. Here, we analyzed striatal transcriptomes in amphetamine-pretreated SHRs (5 mg/kg, i.p. for 7 days [twice daily]), which showed a conditioned place preference to and self-administration of amphetamine. Microarray analyses revealed increased mRNA expression of 55 genes (>1.65-fold increase), while 17 genes were downregulated (<0.6-fold) in the striatum of SHRs. The main functional categories overrepresented among the differentially expressed genes in the striatum include those involved in transcription (e.g., Cebpb, Per2), genes associated with angiogenesis (e.g., Kdr, Klf5), cell adhesion (e.g., Col11a1, Ctgf), apoptosis (e.g., Nfkbia, Perp) and neuronal development (e.g., Egr2, Nr4a3). In conclusion, we dissected the striatal transcriptional responses to the reinforcing effects of repeated amphetamine treatment in the SHR model of ADHD. Future studies should determine the influence of these altered transcripts on amphetamine reinforcement in amphetamine-treated SHRs, and the clinical relevance of the present findings with regard to amphetamine use/abuse in ADHD individuals.


Asunto(s)
Anfetamina/administración & dosificación , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Perfilación de la Expresión Génica/métodos , Animales , Hipertensión/genética , Hipertensión/metabolismo , Masculino , Ratas , Ratas Endogámicas SHR , Autoadministración
18.
J Neurosci Methods ; 252: 48-54, 2015 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-25169048

RESUMEN

BACKGROUND: High novelty seeking has been assumed to predict vulnerability to use addictive drugs. Notably, it is also a symptom associated with attention-deficit/hyperactivity disorder (ADHD). The aim of this study was to identify whether spontaneously hypertensive rats (SHRs), putative animal models of ADHD, display individual differences in novelty-seeking behavior, and whether high novelty-seeking SHRs show enhanced sensitivity to the reinforcing effect of methylphenidate, the most commonly prescribed stimulant ADHD medication. METHODS: First, we established that SHRs show higher levels of novelty-seeking behavior than their normotensive control strain, Wistar Kyoto (WKY) rats. Novelty seeking was measured in two tests: open field test in a novel test arena, and novel object preference tests. Thereafter, SHRs were classified into high responders (HR) or low responders (LR), high novelty-preferring (HNP) or low novelty-preferring (LNP) rats, based on individual scores in the two behavioral assays. Methylphenidate self-administration was assessed thereafter. RESULTS: SHRs showed higher levels of novelty-seeking behavior than WKY rats. HR/LR and HNP/LNP subgroups were identified. HR and LR rats showed comparable rates of methylphenidate self-administration. However, HNP SHRs worked more for methylphenidate infusions than their LNP counterparts. CONCLUSIONS: We showed some evidence on inter-individual variations in novelty seeking in SHRs. Importantly, we demonstrated enhanced sensitivity of HNP SHRs to the reinforcing effect of methylphenidate, indicating a "drug-vulnerable" SHR subpopulation. These findings are important as they may provide basis for a potential screening tool to identify a subset of ADHD patients (i.e. high novelty seekers) who may be at risk for misusing/abusing methylphenidate.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Estimulantes del Sistema Nervioso Central/administración & dosificación , Conducta Exploratoria/efectos de los fármacos , Individualidad , Metilfenidato/administración & dosificación , Refuerzo en Psicología , Animales , Condicionamiento Operante/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Autoadministración
19.
Front Cell Neurosci ; 8: 227, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25165432

RESUMEN

Accumulating preclinical evidence suggests the use of amnion as a source of stem cells for investigations of basic science concepts related to developmental cell biology, but also for stem cells' therapeutic applications in treating human disorders. We previously reported isolation of viable rat amniotic fluid-derived stem (AFS) cells. Subsequently, we recently reported the therapeutic benefits of intravenous transplantation of AFS cells in a rodent model of ischemic stroke. Parallel lines of investigations have provided safety and efficacy of stem cell therapy for treating stroke and other neurological disorders. This review article highlights the need for investigations of mechanisms underlying AFS cells' therapeutic benefits and discusses lab-to-clinic translational gating items in an effort to optimize the clinical application of the cell transplantation for stroke.

20.
Artículo en Inglés | MEDLINE | ID: mdl-24943998

RESUMEN

Fetal alcohol spectrum disorder (FASD) is caused by intrauterine exposure to alcohol and can cause a full range of abnormalities to brain development, as well as long-term sequelae of cognitive, sensory and motor impairments. The incidence is estimated to be as high as 2% to 5% in children born within the US, however the prevalence is even higher in low socioeconomic populations. Despite the various mechanisms thought to explain the etiology of FASD, molecular targets of ethanol toxicity during development are not completely understood. More recent findings explore the role of GABA-A and GABA-B mechanisms, as well as cell death, cell signaling and gene expression malfunctions. Stem cell based therapies have grown exponentially over the last decade, which have lead to novel clinical interventions across many disciplines. Thus, early detailed understanding of the therapeutic potential of stem cell research has provided promising applications across a wide range of illnesses. Consequently, these potential benefits may ultimately lead to a reduced incidence and severity of this highly preventable and prevalent birth defect. It is recognized that stem cell derivations provide unique difficulties and limitations of therapeutic applications. This review will outline the current knowledge, along with the benefits and challenges of stem cell therapy for FASD.


Asunto(s)
Trastornos del Espectro Alcohólico Fetal/terapia , Trasplante de Células Madre/métodos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Encéfalo/patología , Encéfalo/fisiopatología , Trastornos del Espectro Alcohólico Fetal/patología , Trastornos del Espectro Alcohólico Fetal/fisiopatología , Humanos , Trasplante de Células Madre/efectos adversos , Ácido gamma-Aminobutírico/metabolismo
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