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Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress
Publication . Rodrigues, Rui S.; Moreira, João B.; Mateus, Joana; Barateiro, Andreia; Paulo, Sara L; Vaz, Sandra H.; Lourenço, Diogo M.; Ribeiro, Filipa; Soares, Rita; Loureiro-Campos, E.; Bielefeld, P.; Sebastião, Ana M; Fernandes, Adelaide; Pinto, L.; Fitzsimons, C. P.; Xapelli, Sara
Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.
Cannabinoid actions on neural stem cells: implications for pathophysiology
Publication . Rodrigues, Rui S.; Lourenço, Diogo M.; Paulo, Sara L; Mateus, Joana; Ferreira, Miguel F.; Mouro, Francisco; Moreira, João B.; Ribeiro, Filipa; Sebastião, Ana M; Xapelli, Sara
With the increase of life expectancy, neurodegenerative disorders are becoming not only a health but also a social burden worldwide. However, due to the multitude of pathophysiological disease states, current treatments fail to meet the desired outcomes. Therefore, there is a need for new therapeutic strategies focusing on more integrated, personalized and effective approaches. The prospect of using neural stem cells (NSC) as regenerative therapies is very promising, however several issues still need to be addressed. In particular, the potential actions of pharmacological agents used to modulate NSC activity are highly relevant. With the ongoing discussion of cannabinoid usage for medical purposes and reports drawing attention to the effects of cannabinoids on NSC regulation, there is an enormous, and yet, uncovered potential for cannabinoids as treatment options for several neurological disorders, specifically when combined with stem cell therapy. In this manuscript, we review in detail how cannabinoids act as potent regulators of NSC biology and their potential to modulate several neurogenic features in the context of pathophysiology.
Neural stem cells and cannabinoids in the spotlight as potential therapy for epilepsy
Publication . Lourenço, Diogo M.; Ribeiro Rodrigues, Leonor; Sebastião, Ana M; Diógenes, Maria José; Xapelli, Sara
Epilepsy is one of the most common brain diseases worldwide, having a huge burden in society. The main hallmark of epilepsy is the occurrence of spontaneous recurrent seizures, having a tremendous impact on the lives of the patients and of their relatives. Currently, the therapeutic strategies are mostly based on the use of antiepileptic drugs, and because several types of epilepsies are of unknown origin, a high percentage of patients are resistant to the available pharmacotherapy, continuing to experience seizures overtime. Therefore, the search for new drugs and therapeutic targets is highly important. One key aspect to be targeted is the aberrant adult hippocampal neurogenesis (AHN) derived from Neural Stem Cells (NSCs). Indeed, targeting seizure-induced AHN may reduce recurrent seizures and shed some light on the mechanisms of disease. The endocannabinoid system is a known modulator of AHN, and due to the known endogenous antiepileptic properties, it is an interesting candidate for the generation of new antiepileptic drugs. However, further studies and clinical trials are required to investigate the putative mechanisms by which cannabinoids can be used to treat epilepsy. In this manuscript, we will review how cannabinoid-induced modulation of NSCs may promote neural plasticity and whether these drugs can be used as putative antiepileptic treatment.
Uncovering the neurogenic potential of cannabinoids upon adult neural stem modulation : cannabidivarin as a novel modulator of adult neurogenesis
Publication . Lourenço, Diogo M.; Xapelli, Sara Alves
The neurosphere assay : an effective in vitro technique to study neural stem cells
Publication . Xapelli, Sara; Soares, Rita; Ribeiro, Filipa; Lourenço, Diogo M.; Rodrigues, Rui S.; Moreira, João B.; Sebastião, Ana M.; Morais, Vanessa A.
Neural stem cells (NSCs) are known to be present in the adult mammalian brain where they constitutively differentiate into the neuronal, astroglial, and oligodendroglial lineages, in defined processes termed n e u ro ge n e s i s , a st ro g l i o ge n e s i s a n d oligodendrogenesis, respectively (reviewed in Braun and Jessberger, 2014). During brain development, NSCs are present throughout the brain, becoming progressively restricted to defined brain regions. In the adult brain, NSCs are mainly present in areas classically known as neurogenic niches, i.e. the subventricular zone (SVZ), along the lateral walls of the lateral ventricles, and the subgranular zone, located in the dentate gyrus (DG) of the hippocampus. These areas are particularly enriched with NSCs, which not only are multipotent cells but also proliferative cells with the ability to selfrenew, thus maintaining their own pool of cells. In fact, neurogenesis, astrogliogenesis and oligodendrogenesis are highly intricate processes comprising several steps, including proliferation, differentiation, migration, and functional integration of the newly formed cells in the existing circuitry, which are regulated by a plethora of factors. These newly differentiated adult-born cells have the capacity to continuously modulate brain function and plasticity, by constantly reacting to external or internal stimuli (reviewed in Braun and Jessberger, 2014).
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PD/BD/141784/2018