Mitochondria are present in the pre- and post-synaptic regions, providing the energy required for the activity of these very specialized neuronal compartments. Biogenesis of synaptic mitochondria takes place in the cell body, and these organelles are then transported to the synapse by motor proteins that carry their cargo along microtubule tracks. The transport of mitochondria along neurites is a highly regulated process, being modulated by the pattern of neuronal activity and by extracellular cues that interact with surface receptors. These signals act by controlling the distribution of mitochondria and by regulating their activity. Therefore, mitochondria activity at the synapse allows the integration of different signals and the organelles are important players in the response to synaptic stimulation. Herein we review the available evidence regarding the regulation of mitochondrial dynamics by neuronal activity and by neuromodulators, and how these changes in the activity of mitochondria affect synaptic communication.

The adult mammalian brain can produce new neurons in a process called adult neurogenesis, which occurs mainly in the subventricular zone (SVZ) and in the hippocampal dentate gyrus (DG). Brain-derived neurotrophic factor (BDNF) signaling and cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to independently modulate neurogenesis, but how they may interact is unknown. We now used SVZ and DG neurosphere cultures from early (P1-3) postnatal rats to study the CB1R and CB2R crosstalk with BDNF in modulating neurogenesis. BDNF promoted an increase in SVZ and DG stemness and cell proliferation, an effect blocked by a CB2R selective antagonist. CB2R selective activation promoted an increase in DG multipotency, which was inhibited by the presence of a BDNF scavenger. CB1R activation induced an increase in SVZ and DG cell proliferation, being both effects dependent on BDNF. Furthermore, SVZ and DG neuronal differentiation was facilitated by CB1R and/or CB2R activation and this effect was blocked by sequestering endogenous BDNF. Conversely, BDNF promoted neuronal differentiation, an effect abrogated in SVZ cells by CB1R or CB2R blockade while in DG cells was inhibited by CB2R blockade. We conclude that endogenous BDNF is crucial for the cannabinoid-mediated effects on SVZ and DG neurogenesis. On the other hand, cannabinoid receptor signaling is also determinant for BDNF actions upon neurogenesis. These findings provide support for an interaction between BDNF and endocannabinoid signaling to control neurogenesis at distinct levels, further contributing to highlight novel mechanisms in the emerging field of brain repair.

Neurotransmitters are also involved in functions other than conventional signal transfer between nerve cells, such as development, plasticity, neurodegeneration, and neuroprotection. For example, there is a considerable amount of data indicating developmental roles for the glutamatergic, cholinergic, dopaminergic, GABA-ergic, and ATP/adenosine systems. In this review, we discuss the existing literature on these "new" functions of neurotransmitters in relation to some unconventional neurotransmitters, such as the endocannabinoids and nitric oxide. Data indicating both transcriptional and post-transcriptional modulation of endocannabinoid and nitrinergic systems after neural lesions are discussed in relation to the non-conventional roles of these neurotransmitters. Knowledge of the roles of neurotransmitters in brain functions other than information transfer is critical for a more complete understanding of the functional organization of the brain and to provide more opportunities for the development of therapeutical tools aimed at minimizing neuronal death.

Objective: Schizophrenia is a multifactorial disorder. It is known that a combination of extensive multiple common alleles may be involved in its etiology, each contributing with a small to moderate effect, and, possibly, some rare alleles with a much larger effect size. We aimed to perform a systematic review of association studies between schizophrenia (and its subphenotypes) and polymorphisms in the CNR1 gene, which encodes cannabinoid receptors classically implicated in schizophrenia pathophysiology, as well as to present unpublished results of an association study in a Brazilian population. Methods: Two reviewers independently searched for eligible studies and extracted outcome data using a structured form. Papers were retrieved from PubMed and ISI Web of Knowledge using the search term schizophrenia in combination with CNR1 or CB1 or cannabinoid receptor. Twenty-four articles met our inclusion criteria. We additionally present data from a study of our own comparing 182 patients with schizophrenia and 244 healthy controls. Results: No consistent evidence is demonstrated. Conclusion: Some seemingly positive association studies stress the need for further investigations of the possible role of endocannabinoid genetics in schizophrenia.

Although the medicinal use of Cannabis sativa derivatives is well known since antiquity, the study of their properties expanded recently with the discovery of an endogenous cannabinoid system, which comprises the endogenous cannabis-like ligands (endocannabinoids), the cannabinoid receptors (CB1 and CB2) and the enzymes involved in their metabolism. Since the discovery of the endocannabinoid system (ECS), the scientific community focused on research of its clinical use and achieved important findings during the last decade. In some countries, cannabis derivatives are a pharmacological option for appetite stimulation and pain treatment. However, the first ECS-based drug rimonabant (a CB1 antagonist), approved for the treatment obesity with associated risk factors, was withdrawn due to safety concerns. Nowadays, based on the growing evidences resulting from preclinical and clinical studies of ECS modulators, these drugs are currently pointed out as novel therapeutic approaches for several pathophysiological conditions. Here, we review the potential role of (endo)cannabinoid system in therapeutics and the recent designed strategies for the development of drugs that target this system. 

Os recetores acoplados à proteína G (GPCRs) constituem a maior família de recetores membranares, sendo essenciais no controlo de processos fisiológicos e patofisiológicos, como cancro, hipertensão, entre outros. O número de fármacos direcionados para estes recetores tem vindo a aumentar, contando com mais de 475 aprovados pela FDA. Neste estudo focámo-nos em quatro recetores: Recetor Canabinoide 1 (CB1) e 2 (CB2) e recetor acoplado à proteína G 18 (GPR18) e 55 (GPR55), dois recetores órfãos. CB1 e CB2 pertencem à classe A da família de GPCRs. A expressão de CB1 é elevada no sistema nervoso central, enquanto que CB2 é abundante em órgãos periféricos com função imunitária. GPR55 pertence à classe A da família de GPCRs, sendo sugerido como alvo terapêutico na diabetes, obesidade, osteoporose e cancro. GPR18 pertence também à classe A e poderá ser alvo em terapias para cancro e doenças inflamatórias. O objetivo deste estudo consistiu na identificação e avaliação farmacológica de ligandos destes recetores. Estudos anteriores do nosso laboratório identificaram alguns compostos, de uma biblioteca de compostos in-house, capazes de modular a atividade destes recetores. Tendo por base a estrutura molecular destes, fizemos o screening do efeito antagonista e agonista destes novos compostos, pertencentes também à nossa biblioteca. Seguidamente ao screening inicial, foram realizados estudos de seletividade e potência, recorrendo a ensaios de recrutamento de β-arrestina, ligação de radioligandos e acumulação de cAMP. Para o GPR18 foram testadas duas séries de compostos (biblioteca de compostos 1 e 2), enquanto que para o CB2 foi testada apenas uma série de compostos (biblioteca de compostos 3). Os estudos de seletividade foram realizados com GPR55 e CB1, respetivamente. Os nossos resultados identificaram um composto promissor para GPR18 (EC50(composto56)=0.0302±0.004 μM) e um para CB2 (Ki(composto76)=0.339±0.061 µM). No entanto, mais testes devem ser executados, de forma a clarificar se estes compostos conseguem efetivamente modular a atividade destes recetores. Futuramente, será necessária a realização de novos estudos, permitindo compreender como estes compostos modulam a atividade destes recetores e otimizar a mesma, com objetivo de desenvolver novas moléculas a serem usadas como terapêuticas em várias disfunções relacionadas com CB1, CB2, GPR18 e GPR55.

A utilização terapêutica da Cannabis sativa, desde a antiguidade, encontra-se bem documentada e foram-lhe desde sempre atribuídas propriedades curativas. Com a evolução da química e da medicina foi estudada de forma mais exaustiva esta planta, de forma a entender melhor a sua constituição química, o que levou à descoberta das substâncias ativas da planta. Posteriormente, descobriu-se um sistema canabinóide endógeno humano onde essas substâncias atuariam por meio de recetores próprios. Foram também descobertos ligandos endógenos com afinidade para esses recetores, denominados então de endocanabinóides, e compreendida a sua síntese e degradação, e as suas vias de sinalização. Essas descobertas levaram ao conhecimento atual do sistema endocanabinóide. Esta revisão teve como objetivo compreender as bases mecanísticas do sistema endocanabinóide e a sua relação com a dor neuropática, com recurso a ensaios pré-clínicos e ensaios clínicos aleatorizados de duração superior a 2 semanas. Foi efetuada uma análise ao número de publicações indexadas no “Pubmed” entre 1970 e 2018, com a pesquisa das palavras “cannabinoid in therapeutic” que demonstrou o crescente número de publicações sobre esta temática nos últimos anos. Investigações pré-clínicas e clínicas vieram elucidar a relação deste sistema com as mais diversas patologias, entre elas a dor neuropática, contudo, nem sempre com resultados concordantes entre si. Os resultados obtidos nos ensaios clínicos efetuados com substâncias que atuam no sistema endocanabinóide no âmbito da dor neuropática incluídos nesta revisão, demonstram o interesse em continuar a investigar esta ligação. No entanto, devido à discordância entre os ensaios, há a necessidade de serem efetuados ensaios de maior dimensão e duração para aferir a segurança e eficácia destes fármacos no tratamento da dor neuropática.