Structure-activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure-activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 - a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F] 12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F] 12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F] 12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F] 12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F] 12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

The dual effect of acetate on microglial TNF-α production

Abstract Introduction: Short-Chain Fatty Acids (SCFA) are products of intestinal microbial metabolism that can reach the brain and alter microglia in health and disease contexts. However, data are conflicting on the effect of acetate, the most abundant SCFA in the blood, in these cells. Objective: The authors aimed to investigate acetate as a modulator of the inflammatory response in microglia stimulated with LPS. Method: The authors used an immortalized cell line, C8-B4, and primary cells for in vitro treatments with acetate and LPS. Cell viability was analyzed by MTT, cytokine by RT-PCR, ELISA, and flow cytometry. The authors also performed in vivo and in silico analyses to study the role of acetate and the TNF-α contribution to the development of Experimental Autoimmune Encephalomyelitis (EAE). Results: Acetate co-administered with LPS was able to exacerbate the production of pro-inflammatory cytokines at gene and protein levels in cell lines and primary culture of microglia. However, the same effects were not observed when acetate was administered alone or as pretreatment, prior to the LPS stimulus. Additionally, pharmacological inhibition of histone deacetylase concomitantly with acetate and LPS led to decreased TNF-α production. In silico analysis showed a crucial role of the TNF-α pathway in EAE development. Moreover, acetate administration in vivo during the initial phase of EAE led to a better disease outcome and reduced TNF-α production. Conclusion: Treatment with acetate was able to promote the production of TNF-α in a concomitant LPS stimulus of microglia. However, the immune modulation of microglia by acetate pretreatment may be a component in the generation of future therapies for neurodegenerative diseases. HIGHLIGHTS Acetate was able to exacerbate the production of TNF-α in microglia. Acetate administered as pre-treatment to LPS acts as an anti-inflammatory. Histone deacetylase decreased TNF-α production in Acetate- and LPS-treated cells. Depending on the time of administration, Acetate modulates microglia's activation. Acetate may threaten neurodegenerative and neuropsychiatric diseases.

Research progress on Gastrodia elata prevention and treatment neuropsychiatric diseases / 中草药

Gastrodia elata is a kind of precious Chinese materia medica, which showed good effect in the treatment of headache, improve learning and memory, antidepressant, and other neuropharmacology effects. In this paper, the neuropharmacology effects and corresponding chemical constituents of G. elata in the last ten years were summarized and sorted by referring the literature of CNKI and PubMed, as well as inquired the development of G. elata related drugs and health care products in the official website of the Chinese Food and Drug Administration, which provides reference to develop nervous and mental diseases products of G. elata.

Neonatal Administration of Memantine Enhances Social Cognition in Adult Rats Subjected to Early Maternal Deprivation

Schizophrenia is considered a neurodevelopmental disorder; however, all the available treatment options are used when the disease becomes clinically significant in adolescence or early adulthood. Using a developmental rat model of schizophrenia, we examined whether neonatal treatment with memantine, an NMDA receptor modulator, can improve schizophrenic-like symptoms in adulthood. Early maternal deprivation in rats produces deficits in social interaction behaviors in adulthood. In contrast, memantine administrated in neonatal rats subjected to early maternal deprivation significantly reduces deficits in social interaction behaviors in adulthood. These results raise the possibility that pharmacological treatment with memantine at the early developmental stage helps people with a risk to develop schizophrenic-like symptoms.

Neuroprotective Mechanism of Ethanolic Extract of lrvingia gabonensis stem Bark against Cadmium-induced Neurotoxicity in Rats.

Objective: To explore the neuroprotective effect of Irvingia gabonensis (IG) against cadmium-induced oxidative damage in rats brain. Place and Duration of Study: Department of Chemical sciences, (Biochemistry laboratory), Afe Babalola University and Department of Biochemistry, Ekiti State University, Ado Ekiti, Nigeria between February 2014 and May 2014. Methods: The study was performed on twenty (20) male rats divided into four groups: a control group, cadmium group (4mgkg-1day-1, intraperitoneally [i.p.]) and cadmium toxication groups received 200 and 400mgkg-1 body weight of extract by oral gavage for 28 days. The degree of protection in brain tissue was evaluated by the levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase, and catalase. The aminotransferase (ALT), aspartate aminotransferase (AST) activities and histological examination were monitored. Results: Irvingia gabonensis showed a significant (P>.05) brain-protective effect by decreasing the level of lipid peroxidation and elevate the activities of antioxidative enzymes and level of GSH. Furthermore, histological alterations in brain were observed in cadmium untreated rats and were ameliorated in cadmium-induced treated rats with IG. Conclusions: Consequently Irvingia gabonensis blocked oxidative brain damage induced by cadmium in rats. These data suggest that Irvingia gabonensis extract may play a very useful role in reduction of the neurotoxicological damage induced by cadmium.

O uso de filmes como recurso pedagógico no ensino de neurofarmacologia / The use of films as an educational resource on neuropharmacology teaching / El uso de películas como recurso pedagógico en la enseñanza de neurofarmacología

Recursos audiovisuais são estratégias utilizadas para facilitar o processo ensino-aprendizagem. Entretanto, o uso de filmes comerciais como recurso pedagógico para o ensino das ciências da saúde, tal como a farmacologia, não é tão comum. O objetivo deste artigo é relatar nossa experiência com o uso de filmes, como: Linha Mortal, Mr. Jones, Tempo de despertar, entre outros, como ferramenta de ensino da disciplina Neurofarmacologia. Embora seja ministrada para o ensino de graduação do curso de Enfermagem da Universidade de Brasília, a metodologia pode ser adotada em outros cursos da área de Ciências da Saúde. A combinação de referencial teórico de Neurofarmacologia e a discussão dos filmes em sala de aula pode ser comparada a um estudo de caso, cuja narrativa permite aproximar os estudantes da realidade, tornando lúdico e fácil de relacionar as situações clínicas com o tratamento farmacológico, além de assimilarem novos conceitos.

Audiovisual resources are strategies used to facilitate the process of teaching. However, the use of commercial films as an educational resource for teaching health sciences, such as pharmacology, is not very common. The purpose of this article is to describe our experience with using films, as Flatliners, Mr. Jones, Awakenings, among others, as a teaching tool for the Neuropharmacology course. Although it is used to teach undergraduates at the Nursing course of Brasília University, the methodology can be adopted by other courses in the field of Health Sciences. The combination of the theoretical framework of Neuropharmacology and the classroom discussion of the films can be compared to a case study, whose narrative allows the students to be brought closer to reality, making it entertaining and easier for them to relate to clinical situations, with pharmacotherapy, and to assimilate new concepts.

Los recursos audiovisuales son estrategias para facilitar el proceso de enseñanza-aprendizaje. El uso de películas comerciales como recurso pedagógico para la enseñanza de las ciencias de la salud, tal como la farmacología, no es tan común. El objetivo de este artículo es relatar nuestra experiencia al usar películas, como, Línea Mortal, Mr. Jones, Tiempo de despertar, entre otras, como herramienta de enseñanza de la asignatura de Neurofarmacología. Aunque se utilice para la enseñanza del curso de graduación de Enfermería de la Universidad de Brasilia, la metodología se puede adoptar en otros cursos de las Ciencias de la Salud. La combinación del referencial teórico de Neurofarmacología y la discusión de las películas en clases se puede comparar a un estudio del caso, cuya narrativa permite aproximar los estudiantes a la realidad, volviendo lúdico y más fácil relacionar las situaciones clínicas con el tratamiento farmacológico y assimilar nuevos conceptos.

Neurobiology of Attention-Deficit/Hyperactivity Disorder and the Action Mechanism of OROS Methylphenidate

This article is to review neurobiology of attention-deficit/hyperactivity disorder (ADHD) and pharmacological properties of Osmotic-Controlled Release Oral delivery System Methylphenidate (OROS MPH)(Concerta Oros(R)) in celebration of its one-decade clinical experiences in Korea. ADHD is a highly heritable neurodevelopmental disorder, characterized by age-inappropriate inattention, hyperactivity and impulsiveness. The symptoms of ADHD are consistent with dysfunction of the prefrontal cortex (PFC). The PFC functions such as working memory and executive function are powerfully modulated by the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE). Methylphenidate (MPH) is a first line treatment for children and adolescents with ADHD in Korea. MPH improves the PFC functions with the mechanism of action being modulation of DA and NE tones by blocking both dopamine transporter (DAT) and norepinephrine transporter (NET). Stimulation of D1 and NE alpha2 receptors on the postsynaptic neurons may be its main mechanisms of action which improve working memory and behavioral inhibition in patients with ADHD. OROS MPH, one of long-acting MPH, employs an osmotic-releasing oral system (OROS), which has been designed to have 12 hour duration of effect, which permits oncedaily dosing, which has been shown to be as effective as 3-times-a-day immediate-release formulation of MPH (IR MPH). Recently there is growing evidence that OROS MPH has positive effects even on adults with ADHD, in multidimensional aspects; cognitively, emotionally and functionally.

Neurobiology of Attention-Deficit/Hyperactivity Disorder and the Action Mechanism of OROS Methylphenidate

This article is to review neurobiology of attention-deficit/hyperactivity disorder (ADHD) and pharmacological properties of Osmotic-Controlled Release Oral delivery System Methylphenidate (OROS MPH)(Concerta Oros(R)) in celebration of its one-decade clinical experiences in Korea. ADHD is a highly heritable neurodevelopmental disorder, characterized by age-inappropriate inattention, hyperactivity and impulsiveness. The symptoms of ADHD are consistent with dysfunction of the prefrontal cortex (PFC). The PFC functions such as working memory and executive function are powerfully modulated by the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE). Methylphenidate (MPH) is a first line treatment for children and adolescents with ADHD in Korea. MPH improves the PFC functions with the mechanism of action being modulation of DA and NE tones by blocking both dopamine transporter (DAT) and norepinephrine transporter (NET). Stimulation of D1 and NE alpha2 receptors on the postsynaptic neurons may be its main mechanisms of action which improve working memory and behavioral inhibition in patients with ADHD. OROS MPH, one of long-acting MPH, employs an osmotic-releasing oral system (OROS), which has been designed to have 12 hour duration of effect, which permits oncedaily dosing, which has been shown to be as effective as 3-times-a-day immediate-release formulation of MPH (IR MPH). Recently there is growing evidence that OROS MPH has positive effects even on adults with ADHD, in multidimensional aspects; cognitively, emotionally and functionally.

A systematic review of the neurobiological aspects of memory in the aging process / Revisão sistemática dos aspectos neurobiológicos da memória no processo de envelhecimento

A systematic review of the neuroanatomical literature was performed to determine the neuropharmacological aspects most relevant to the study of memory processes. Articles were retrieved using the search terms "biology of memory", "memory and aging", "memory impairment", "elderly and memory," and their equivalents in Portuguese. Of the studies surveyed, five studies dealt with epidemiological and demographic issues, 12 were clinical trials i.e. were based on testing and implementation of instruments in human subjects, 33 studies were basic research involving studies of mice, rats and non-human primates, and biochemical and in vitro trials and finally, 52 studies were literature reviews or book chapters which in our view, fell into this category. Conclusions: The work sought to highlight which neural networks are most involved in processing information, as well as their location within brain regions and the way in which neurotransmitters interact with each other for the formation of these memories. Moreover, it was shown how memory changes during the normal human aging process, both positively and negatively, by analyzing the morphological alterations that occur in the brain of aging individuals.

Buscou-se verificar na literatura os aspectos neuroanatômicos e neurofarmacológicos mais relevantes no estudo dos processos de memória, através de revisão sistemática. O levantamento bibliográfico foi realizado utilizando-se os termos "biology of memory", "memory and aging", "memory impairment", "elderly and memory", e seus correspondentes em português. Dos estudos levantados, cinco estudos tratavam sobre questões epidemiológicas e demográficas; 12 estudos eram de base clínica, ou seja, as pesquisas ocorreram com base em testes e aplicação de instrumentos em seres humanos; 33 estudos foram oriundos da pesquisa básica, envolvendo pesquisas com camundongos, ratos e primatas não humanos, e ensaios bioquímicos e in vitro; e, por fim, 52 estudos são revisões da literatura ou capítulos de livros que, a nosso ver, enquadram-se nesta categoria. Conclusões: Buscou-se dar destaque para quais redes neurais estão mais envolvidas no processamento das informações, bem como sua localização dentro das regiões cerebrais e a forma com a qual os neurotransmissores interagem entre si e atuam para a formação destas memórias. Ademais, mostrou-se como a memória se altera ao longo do processo de envelhecimento humano normal, negativa e positivamente, analisando as alterações morfológicas que ocorrem no cérebro do indivíduo que envelhece.

Wellbutrin SR in Depression / 대한정신약물학회지

This article discusses the mechanism of action of Wellbutrin (bupropion) and relates the drug's neuropharmacologic effects to its clinical efficacy and side effect profiles. The preclinical and clinical data show that bupropion acts via dual inhibition of norepinephrine and dopamine reuptake and is devoid of clinically significant serotonergic effects or direct effects on postsynaptic receptors. With respect to treatment of depression, these catecholaminergic effects of bupropion tended to produce more robust effects on anhedonia/positive affect. Augmenting or switching antidepressants with bupropion has become an increasingly common strategy in the treatment of resistant depression. Bupropion has been suggested for the treatment of bipolar depression , because of its efficacy and a lower risk of inducing switches to hypomania or mania. Clinically, SR formulation, side effects are infrequent and benign, would be used without a risk of seizure in dose up to 400 mg/day.