Phosphodiesterase7 Inhibition Activates Adult Neurogenesis in Hippocampus and Subventricular Zone In Vitro and In Vivo.

The phosphodiesterase 7 (PDE7) enzyme is one of the enzymes responsible for controlling intracellular levels of cyclic adenosine 3',5'-monophosphate in the immune and central nervous system. We have previously shown that inhibitors of this enzyme are potent neuroprotective and anti-inflammatory agents. In addition, we also demonstrated that PDE7 inhibition induces endogenous neuroregenerative processes toward a dopaminergic phenotype. Here, we show that PDE7 inhibition controls stem cell expansion in the subgranular zone of the dentate gyrus of the hippocampus (SGZ) and the subventricular zone (SVZ) in the adult rat brain. Neurospheres cultures obtained from SGZ and SVZ of adult rats treated with PDE7 inhibitors presented an increased proliferation and neuronal differentiation compared to control cultures. PDE7 inhibitors treatment of neurospheres cultures also resulted in an increase of the levels of phosphorylated cAMP response element binding protein, suggesting that their effects were indeed mediated through the activation of the cAMP/PKA signaling pathway. In addition, adult rats orally treated with S14, a specific inhibitor of PDE7, presented elevated numbers of proliferating progenitor cells, and migrating precursors in the SGZ and the SVZ. Moreover, long-term treatment with this PDE7 inhibitor shows a significant increase in newly generated neurons in the olfactory bulb and the hippocampus. Also a better performance in memory tests was observed in S14 treated rats, suggesting a functional relevance for the S14-induced increase in SGZ neurogenesis. Taken together, our results indicate for the first time that inhibition of PDE7 directly regulates proliferation, migration and differentiation of neural stem cells, improving spatial learning and memory tasks. Stem Cells 2017;35:458-472.

Complement component 3 (C3) expression in the hippocampus after excitotoxic injury: role of C/EBPß.

BACKGROUND: The CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor implicated in the control of proliferation, differentiation, and inflammatory processes mainly in adipose tissue and liver; although more recent results have revealed an important role for this transcription factor in the brain. Previous studies from our laboratory indicated that CCAAT/enhancer-binding protein ß is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. More recently, we have shown that the complement component 3 gene (C3) is a downstream target of CCAAT/enhancer-binding protein ß and it could be a mediator of the proinflammatory effects of this transcription factor in neural cells. METHODS: Adult male Wistar rats (8-12 weeks old) were used throughout the study. C/EBPß+/+ and C/EBPß-/- mice were generated from heterozygous breeding pairs. Animals were injected or not with kainic acid, brains removed, and brain slices containing the hippocampus analyzed for the expression of both CCAAT/enhancer-binding protein ß and C3. RESULTS: In the present work, we have further extended these studies and show that CCAAT/enhancer-binding protein ß and C3 co-express in the CA1 and CA3 regions of the hippocampus after an excitotoxic injury. Studies using CCAAT/enhancer-binding protein ß knockout mice demonstrate a marked reduction in C3 expression after kainic acid injection in these animals, suggesting that indeed this protein is regulated by C/EBPß in the hippocampus in vivo. CONCLUSIONS: Altogether these results suggest that CCAAT/enhancer-binding protein ß could regulate brain disorders, in which excitotoxic and inflammatory processes are involved, at least in part through the direct regulation of C3.

CCAAT/enhancer binding protein ß directly regulates the expression of the complement component 3 gene in neural cells: implications for the pro-inflammatory effects of this transcription factor.

BACKGROUND: The CCAAT/enhancer-binding protein ß (C/EBPß) is a transcription factor, which was first identified as a regulator of differentiation and inflammatory processes mainly in adipose tissue and liver; however, its function in the brain was largely unknown for many years. Previous studies from our laboratory indicated that C/EBPß is implicated in inflammatory process and brain injury, since mice lacking this gene were less susceptible to kainic acid-induced injury. METHODS: We first performed cDNA microarrays analysis using hippocampal RNA isolated from C/EBPß (+/+) and C/EBPß (-/-) mice. Immunocytochemical and immunohistochemical studies were done to evaluate C/EBPß and C3 levels. Transient transfection experiments were made to analyze transcriptional regulation of C3 by C/EBPß. To knockdown C/EBPß and C3 expression, mouse astrocytes were infected with lentiviral particles expressing an shRNA specific for C/EBPß or an siRNA specific for C3. RESULTS: Among the genes displaying significant changes in expression was complement component 3 (C3), which showed a dramatic decrease in mRNA content in the hippocampus of C/EBPß (-/-) mice. C3 is the central component of the complement and is implicated in different brain disorders. In this work we have found that C/EBPß regulates C3 levels in rodents glial in vitro and in the rat Substantia nigra pars compacta (SNpc) in vivo following an inflammatory insult. Analysis of the mouse C3 promoter showed that it is directly regulated by C/EBPß through a C/EBPß consensus site located at position -616/-599 of the gene. In addition, we show that depletion of C/EBPß by a specific shRNA results in a significant decrease in the levels of C3 together with a reduction in the increased levels of pro-inflammatory agents elicited by lipopolysaccharide treatment. CONCLUSIONS: Altogether, these results indicate that C3 is a downstream target of C/EBPß, and it could be a mediator of the pro-inflammatory effects of this transcription factor in neural cells.

A spontaneous deletion of α-synuclein is associated with an increase in CB1 mRNA transcript and receptor expression in the hippocampus and amygdala: effects on alcohol consumption.

α-Synuclein (α-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α-syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α-syn gene (C57BL/6(Snca-/-) ) and their respective controls (C57BL/6(Snca) (+/) (+) ). These animals were monitored for spontaneous alcohol consumption (3-10%) and their response to a hypnotic-sedative dose of alcohol (3 g kg(-1) ) was also assessed. Compared with the C57BL/6(Snca+/+) mice, we found that the C57BL/6(Snca-/-) mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6(Snca-/-) mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions.

Papillary Renal Neoplasm With Reverse Polarity: A Clinical, Pathologic, and Molecular Study of 8 Renal Tumors From a Single Institution.

CONTEXT.­: In 2019, papillary renal neoplasm with reverse polarity (PRNRP) was defined as a new neoplasm because it has a predominately tubulopapillary pattern lined by a single layer of cuboidal and eosinophilic cells with apically located round nuclei. Immunohistochemically, this neoplasm showed expression of GATA-3 and L1CAM and had recurrent KRAS mutations. OBJECTIVE.­: To estimate the incidence of PRNRP and provide 8 additional cases with some variations in the morphology. DESIGN.­: We reviewed 1627 renal tumors from our hospital during a 21-year period (2000-2020). We reexamined 196 papillary renal cell carcinomas and selected those that met the diagnostic criteria for PRNRP. RESULTS.­: We found 8 cases consistent with PRNRP. The median age of the patients was 64.75 years; 7 patients were male, and 1 was female. Two patients had end-stage renal disease. No recurrence, metastasis, or tumor-related death occurred in a mean follow-up period of 67.62 months. Tumor size ranged from 1.6 to 3.7 cm. All cases were pT1. Seven cases (7 of 8; 87.5%) had predominantly cystic changes, and 1 had solid architecture. No foamy cells, clear cell change, or psammoma bodies were seen in any cases. All cases were positive for CK7, EMA, GATA3, and L1CAM. KRAS gene mutation was detected in 5 cases (5 of 8; 62.5%). CONCLUSIONS.­: PRNRP represents 4.08% (8 of 196 cases) of papillary renal cell carcinomas and 0.49% (8 of 1627 cases) of all renal tumors in the 21-year period in our series. In our study, all cases exhibited an indolent clinical course. This supports that PRNRP has characteristic morphologic and molecular features.

Cardiac Metastasis From Solid Cancers: A 35-Year Single-Center Autopsy Study.

CONTEXT.­: Cardiac metastases are more prevalent than primary cardiac tumors, and although rare, the incidence is anticipated to increase with the extended survival of oncology patients. OBJECTIVE.­: To estimate the current incidence of cardiac metastasis from solid tumors in adult autopsies. DESIGN.­: Adult autopsy cases from 1984 through 2019 from patients diagnosed with any type of solid cancer were retrieved. The medical charts and pathologic autopsy data were reviewed in detail. RESULTS.­: A total of 1294 adult autopsies performed on patients diagnosed with any type of cancer within the past 35 years were reviewed. We found 124 secondary cardiac tumors. Eighty-five were due to cardiac involvement by solid tumors. Of these, 61 were true cardiac metastases of solid cancers. We focused on these 61 cases. The age range was 32 to 85 years. Forty-four patients were men and 17 were women. The lung was the most common primary site, with 21 cases (34.43%). The most frequent histologic type was carcinoma, with 54 cases (88.52%). The predominant layer of the heart involved was the pericardium, with 35 cases (57.38%). Twenty-one cases (34.43%) had pericardial effusion, with 4 being hemorrhagic. All cases had multiple extracardiac metastases, with 56 cases (91.8%) having distant metastases in 4 or more different organs. CONCLUSIONS.­: Cardiac metastasis is a rare occurrence, with an incidence of 4.71% (61 of 1294 cases) in our series. Lung cancer accounted for most of the cardiac metastases seen, and carcinomas were the most frequent histologic type. The pericardium was the most frequent location. Cardiac metastases occurred most frequently in cases of massive metastatic dissemination.

The new iminothiadiazole derivative VP1.14 ameliorates hippocampal damage after an excitotoxic injury.

Increased levels of glutamate causing excitotoxic damage accompany many neurological disorders. A well-characterized model of excitotoxic damage involves administration of kainic acid (KA), which causes limbic seizure activity and subsequent neuronal death, particularly in the CA1 and CA3 areas of the hippocampus. Inhibition of the enzyme glycogen synthase kinase-3 (GSK-3) and cAMP levels might play an important role in neuroprotection. As intracellular cAMP levels depend, in part, on the activity of the phosphodiesterase enzymes (PDEs), these enzymes have recently emerged as potential therapeutic targets for the treatment of several diseases. In previous works, we have shown a potent anti-inflammatory and neuroprotective effect of GSK-3 inhibition in a model of excitotoxicity, as well as a reduction of nigrostriatal dopaminergic neuronal cell death after phosphodiesterase 7 inhibition, which leads to an increase in cAMP levels. This study was undertaken to determine whether simultaneous inhibition of GSK-3 and PDE-7 by a novel 5-imino-1,2,4-thiadiazole compound, named VP1.14, could prevent the massive neuronal loss in the hippocampus evoked by intrahippocampal injection of KA. Here, we show that rats treated with VP1.14 showed a reduced inflammatory response after KA injection, and exhibited a significant reduction in pyramidal cell loss in the CA1 and CA3 areas of the hippocampus. Studies with hippocampal HT22 cells in vitro also showed a clear neuroprotective effect of VP1.14 and an anti-inflammatory effect shown by a decrease in the nitrite liberation and in the expression of pro-inflammatory cytokines by primary cultures of astrocytes treated with lipopolysaccharide.

Neuroprotective and Anti-Inflammatory Effects of Linoleic Acid in Models of Parkinson's Disease: The Implication of Lipid Droplets and Lipophagy.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease after Alzheimer's disease. The principal pathological feature of PD is the progressive loss of dopaminergic neurons in the ventral midbrain. This pathology involves several cellular alterations: oxidative stress, mitochondrial dysfunction, loss of proteostasis, and autophagy impairment. Moreover, in recent years, lipid metabolism alterations have become relevant in PD pathogeny. The modification of lipid metabolism has become a possible way to treat the disease. Because of this, we analyzed the effect and possible mechanism of action of linoleic acid (LA) on an SH-SY5Y PD cell line model and a PD mouse model, both induced by 6-hydroxydopamine (6-OHDA) treatment. The results show that LA acts as a potent neuroprotective and anti-inflammatory agent in these PD models. We also observed that LA stimulates the biogenesis of lipid droplets and improves the autophagy/lipophagy flux, which resulted in an antioxidant effect in the in vitro PD model. In summary, we confirmed the neuroprotective effect of LA in vitro and in vivo against PD. We also obtained some clues about the novel neuroprotective mechanism of LA against PD through the regulation of lipid droplet dynamics.

Glomerular Diseases in the Colombian Caribbean: Data from the Colombian Nephropathy Registry (NEFRORED®).

Our study aimed to describe the glomerular diseases, both primary glomerular disease (PGD) and secondary glomerular disease (SGD) in the Colombian Caribbean based on the first regional Colombian Nephropathy Registry (NEFRORED®). A descriptive and retrospective study of adult patients with glomerular diseases from the Colombian Caribbean region was made. All diagnoses by renal biopsy with light microscopy and immunofluorescence obtained between January 2008 and June 2018 were recorded. Eight hundred and seventy-one renal biopsies were obtained. The main clinical indication for biopsy was nephritic syndrome (36%). SGD was more frequent than PGD (55% vs. 45%). Within SGD group, lupus nephritis (LN) was the most frequent etiology (83%). Within PGD group, membranous nephropathy (33%) and focal segmental glomerulosclerosis (FSGS) (19%) were the most common glomerular diseases. At a 24-month follow-up, the patients with FSGS and paraproteinemia-mediated glomerular disease had the worst renal survival prognosis. This is the first Colombian Nephropathy Registry in a Caribbean population, demonstrating a high predominance of SGD due to LN.

Peroxisome proliferator-activated receptor γ ligands regulate neural stem cell proliferation and differentiation in vitro and in vivo.

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological and pathological situations. Its role in the central nervous system has been under intense analysis during the last years. Here we show a novel function for PPARγ in controlling stem cell expansion in the adult mammalian brain. Adult rats treated with pioglitazone, a specific ligand of PPARγ, had elevated numbers of proliferating progenitor cells in the subventricular zone and the rostral migratory stream. Electron microscopy analysis also showed important changes in the subventricular zone ultrastructure of pioglitazone-treated animals including an increased number of migratory cell chains. These results were further confirmed in vitro. Neurosphere assays revealed significant increases in the number of neurosphere forming cells from pioglitazone- and rosiglitazone (two specific ligands of PPARγ receptor)-treated cultures that exhibited enhanced capacity for cell migration and differentiation. The effects of pioglitazone were blocked by the PPARγ receptor antagonists GW9662 and T0070907, suggesting that its effects are mediated by a mechanism dependent on PPARγ activation. These results indicate for the first time that activation of PPARγ receptor directly regulates proliferation, differentiation, and migration of neural stem cells in vivo.

Population Kidney Health. A New Paradigm for Chronic Kidney Disease Management.

Statistical data extracted from national databases demonstrate a continuous growth in the incidence and prevalence of chronic kidney disease (CKD) and the ineffectiveness of current policies and strategies based on individual risk factors to reduce them, as well as their mortality and costs. Some innovative programs, telemedicine and government interest in the prevention of CKD did not facilitate timely access to care, continuing the increased demand for dialysis and transplants, high morbidity and long-term disability. In contrast, new forms of kidney disease of unknown etiology affected populations in developing countries and underrepresented minorities, who face socioeconomic and cultural disadvantages. With this background, our objective was to analyze in the existing literature the effects of social determinants in CKD, concluding that it is necessary to strengthen current kidney health strategies, designing in a transdisciplinary way, a model that considers demographic characteristics integrated into individual risk factors and risk factors population, incorporating the population health perspective in public health policies to improve results in kidney health care, since CKD continues to be an important and growing contributor to chronic diseases.

[Intraepidermal Merkel cell carcinoma with INSM1 expression. A case report]. / Carcinoma de Merkel intraepidérmico. Presentación de un caso con expresión de INSM1.

We report the case of a 90-year-old male who presented with an erythematous desquamative plaque on his left cheek. Histopathology demonstrated an epidermal lesion with multifocal epithelial growth. The cells were small, with scant cytoplasm and hyperchromatic nuclei with molding and a high mitotic and apopototic rate. Immunohistochemistry showed positivity for CK20, CK7, synaptophysin and INMS1. These findings are consistent with a Merkel cell carcinoma in situ. This tumor corresponds to a primary neuroendocrine neoplasm of the skin, which usually affects elderly people with sun-exposed skin. Usually, it presents as a dermal tumor but intraepidermal involvement alone is extremely rare. In this scenario, a broad differential diagnosis should be considered, excluding all neoplasms that may present intraepidermal forms. The evolution of this entity is unknown.

Phosphodiesterase 7 Regulation in Cellular and Rodent Models of Parkinson's Disease.

Parkinson's disease is characterized by a loss of dopaminergic neurons in the ventral midbrain. This disease is diagnosed when around 50% of these neurons have already died; consequently, therapeutic treatments start too late. Therefore, an urgent need exists to find new targets involved in the onset and progression of the disease. Phosphodiesterase 7 (PDE7) is a key enzyme involved in the degradation of intracellular levels of cyclic adenosine 3', 5'-monophosphate in different cell types; however, little is known regarding its role in neurodegenerative diseases, and specifically in Parkinson's disease. We have previously shown that chemical as well as genetic inhibition of this enzyme results in neuroprotection and anti-inflammatory activity in different models of neurodegenerative disorders, including Parkinson's disease. Here, we have used in vitro and in vivo models of Parkinson's disease to study the regulation of PDE7 protein levels. Our results show that PDE7 is upregulated after an injury both in the human dopaminergic cell line SH-SY5Y and in primary rat mesencephalic cultures and after lipopolysaccharide or 6-hidroxydopamine injection in the Substantia nigra pars compacta of adult mice. PDE7 increase takes place mainly in degenerating dopaminergic neurons and in microglia cells. This enhanced expression appears to be direct since 6-hydroxydopamine and lipopolysaccharide increase the expression of a 962-bp fragment of its promoter. Taking together, these results reveal an essential function for PDE7 in the pathways leading to neurodegeneration and inflammatory-mediated brain damage and suggest novel roles for PDE7 in neurodegenerative diseases, specifically in PD, opening the door for new therapeutic interventions.

COVID-19 in hemodialysis patients in Colombia: Report of seven cases / [COVID-19 en pacientes en hemodiálisis en Colombia: reporte de siete casos].

At the end of 2019, in Wuhan, China, the outbreak of a new coronavirus began and quickly spread throughout the world infecting and claiming thousands of lives. To date, certain comorbidities are known to be risk factors for unsatisfactory disease outcomes, but little has been reported regarding hemodialysis patients despite being a population at high risk of infection, complications, and death. Here we describe the clinical course, clinical manifestations and complications of COVID-19 in seven patients on permanent hemodialysis. We also make recommendations for the management of patients with chronic kidney disease.

A finales del 2019 se inició en Wuhan, China, el brote de un nuevo coronavirus que se dispersó por todo el mundo infectando y cobrando miles de vidas. Se ha encontrado que ciertas comorbilidades constituyen factores de riesgo para resultados poco satisfactorios de la enfermedad, pero es poco lo que se ha descrito sobre pacientes en hemodiálisis, a pesar de tratarse de una población de alto riesgo de infección, complicaciones y muerte. En este artículo se describe el curso clínico, las manifestaciones clínicas y las complicaciones de la COVID-19 en siete pacientes en hemodiálisis permanente y se hacen recomendaciones para el manejo de pacientes con enfermedad renal crónica.

Anticonvulsant and neuroprotective effects of the novel calcium antagonist NP04634 on kainic acid-induced seizures in rats.

Kainic acid (KA)-induced status epilepticus (SE) is a well-characterized model of excitotoxic neuronal injury. Excitotoxicity results from activation of specific glutamate receptors, with resultant elevation of intracellular Ca(2+). The CA1 and CA3 subregions of the hippocampus are especially vulnerable to KA, and this pattern of neuronal injury resembles that occurring in patients with temporal lobe epilepsy. Calcium plays an essential role in excitotoxicity, and accordingly calcium channel inhibitors have been shown to have protective effects in various experimental models of epilepsy and brain injury. Moreover, they also potentiate the antiseizure efficacy of conventional antiepileptic drugs. This study was undertaken to determine whether NP04634, a novel compound, reported as a non-L-type voltage-sensitive calcium channel (VSCC) inhibitor, could prevent the entrance in SE and the neuronal loss evoked by intraperitoneal injection of KA. Our results show that intragastrical administration of NP04634 reduced the percentage of rats that entered SE after KA injection, increased the latency of SE entry, and significantly reduced the mortality of rats that entered SE. Also, NP04634 prevented the loss of hippocampal CA1 and CA3 pyramidal neurons and reduced the gliosis induced by KA. These results point to a potential anticonvulsant and neuroprotective role for NP04634.

[Bladder leiomiosarcoma. A new case and a review of the literatura]. / Leiomiosarcoma vesical. Presentación de un nuevo caso y revisión de la literatura.

Bladder Leiomiosarcomas are exceptional mesenchimal tumours. Their differential diagnosis is basic to decide our therapeutic attitude. We present a new case of bladder leiomiosarcoma with a bad behavior and with multiple relapses, and perform a review of the literature in order to establish more properly the therapeutic attitudes.

[Prostatic lymphoma and review of the literature]. / Linfoma prostático y revisión de la literatura.

Prostatic lymphoma is an exceptional pathology, that usually is diagnosed because its prostatic symthomatology or as consequence of its invasion by an extraprostatic lymphoma. We present a case of a patient affected by a prostatic lymphoma and we perform a review of the literature in order to establish the diagnostic and therapeutic steps.

NP031112, a thiadiazolidinone compound, prevents inflammation and neurodegeneration under excitotoxic conditions: potential therapeutic role in brain disorders.

Inflammation and neurodegeneration coexist in many acute damage and chronic CNS disorders (e.g., stroke, Alzheimer's disease, Parkinson's disease). A well characterized animal model of brain damage involves administration of kainic acid, which causes limbic seizure activity and subsequent neuronal death, especially in the CA1 and CA3 pyramidal cells and interneurons in the hilus of the hippocampus. Our previous work demonstrated a potent anti-inflammatory and neuroprotective effect of two thiadiazolidinones compounds, NP00111 (2,4-dibenzyl-[1,2,4]thiadiazolidine-3,5-dione) and NP01138 (2-ethyl-4-phenyl-[1,2,4]thiadiazolidine-3,5-dione), in primary cultures of cortical neurons, astrocytes, and microglia. Here, we show that injection of NP031112, a more potent thiadiazolidinone derivative, into the rat hippocampus dramatically reduces kainic acid-induced inflammation, as measured by edema formation using T2-weighted magnetic resonance imaging and glial activation and has a neuroprotective effect in the damaged areas of the hippocampus. Last, NP031112-induced neuroprotection, both in vitro and in vivo, was substantially attenuated by cotreatment with GW9662 (2-chloro-5-nitrobenzanilide), a known antagonist of the nuclear receptor peroxisome proliferator-activated receptor gamma, suggesting that the effects of NP031112 can be mediated through activation of this receptor. As such, these findings identify NP031112 as a potential therapeutic agent for the treatment of neurodegenerative disorders.

Implication of the endocannabinoid system in the locomotor hyperactivity associated with congenital hypothyroidism.

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB(1)) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB(1) receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB(1) receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.