Cannabinoid Actions on Neural Stem Cells : Implications for Pathophysiology, Rui S. Rodrigues et al., 2019

Cannabinoid Actions on Neural Stem Cells : Implications for Pathophysiology

Rui S. Rodrigues, Diogo M. Lourenço, Sara L. Paulo, Joana M. Mateus, Miguel F. Ferreira, Francisco M. Mouro, João B. Moreira, Filipa F. Ribeiro, Ana M. Sebastião and Sara Xapelli

Molecules, 2019, 24, 1350, 59 pp.

Abstract :

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.

Keywords : cannabinoids; neural stem cells; neurogenesis; regeneration; pathophysiology

1. Introduction
The development of a multicellular organism can be compared to a choreographed dance of cellular and molecular interactions involving cell reorganization during precise stages. Although in most regions of the mammalian brain the production of neurons is largely confined to the prenatal period, in specific brain regions, neurogenesis occurs postnatally and continues into adulthood.

In the mammalian central nervous system (CNS), neural stem cells (NSCs) are characterized by their self-renewal capability and multipotency, i.e., the ability to give rise to both neurons and glial cells, such as oligodendrocytes and astrocytes. A “neurogenic niche” can be defined as a complex microenvironment that supports NSCs and their progeny, helping to determine whether NSCs remain dormant or divide, by providing signals that guide early stages of proliferation or differentiation. One of these signals has been shown to come through the action of endocannabinoids (eCBs), mainly via activation of cannabinoid receptors type 1 and 2 (CB1R and CB2R). Cannabinoid research has been capturing the interest of physicians, researchers, pharmaceutical companies and of the general population worldwide because of its broad range of applications. Importantly, increasing data has been showing an important role for cannabinoids in NSC modulation, which might allow combining their wide range of actions with the multitude of applications that stem cells offer. In this review, we provide a summary of cannabinoid actions and its effects in NSC modulation both in development and in the adult brain, highlighting the role of cannabinoids in pathophysiology and as therapeutic agents for neuroregeneration.

2. Endocannabinoid System and Cannabinoids
Cannabis has long been used by humans due to its therapeutic value, for recreational and religious purposes, to produce food for livestock and, for its fibers, to manufacture clothing [1]. Nowadays, a growing body of scientific evidence has been attesting the immense potential of this plant to ameliorate symptoms of several diseases. Indeed, medical-cannabis is being used or proposed to treat neuropathic pain and muscle spasticity associated with multiple sclerosis (MS), neurodevelopmental forms of refractory epilepsy, neurodegenerative and chronic diseases [1–10]. Additionally, there is strong scientific support for its use in eating disorders, to reduce vomiting and nausea associated with chemotherapy, and to alleviate human immunodeficiency virus infection and acquired immune deficiency syndrome (HIV/AIDS) related weight loss [1].

On the other hand, chronic consumption or therapeutic exposure to cannabis can be related with detrimental health effects. Specifically, heavy and sustained cannabis use is associated with cognitive and memory impairments, increased probability of developing schizophrenia-spectrum disorders, acute psychosis and mania [11–15]. Regular cannabis abuse can result in chronic bronchitis and impaired respiratory function if consumed through inhalation. It can also induce physical and significant mental dependence, tolerance and withdrawal symptoms [1,16]. Therefore, one of the challenges of cannabis research is to find ways to prevent the negative side-effects associated with cannabis-based medicines [17,18].

According to the World Drug Report 2017, marijuana (dried leaves, flowers, stems and seeds from the Cannabis sativa or Cannabis indica plants) is consumed by up to 238 million people worldwide, making it, by far, the most widely used drug [19]. The psychoactive effects of cannabis consumption include euphoria, appetite stimulation, sedation, altered perception, impairments in motor control and memory deficits [20]. These effects are almost exclusively related with the presence of D9-tetrahydrocannabinol (D9-THC), which was firstly isolated in its pure form and structurally described in 1964 [21]. Regardless of its psychoactive effects, D9-THC has therapeutic value and unique applications [22].

More than 120 phytocannabinoids (natural occurring cannabinoids) have now been identified as constituents of the cannabis plant [23]. Besides D9-THC, the most abundant cannabinoids present in the cannabis plant are D8-tetrahydrocannabinol (D8-THC), cannabinol (CBN), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), D9-tetrahydrocannabivarin (THCV), cannabivarin (CBV) and cannabidivarin (CBDV) [23].