The neuroprotection of cannabidiol against MPP + -induced toxicity in PC12 cells involves trkA receptors, upregulation of axonal and synaptic proteins, neuritogenesis, and might be relevant to Parkinson's disease

Abstract

Cannabidiol (CBD) is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases. Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. We investigated the involvement of neuritogenesis, NGF receptors (trkA), NGF, and neuronal proteins in the mechanism of neuroprotection of CBD against MPP(+) toxicity in PC12 cells. CBD increased cell viability, differentiation, and the expression of axonal (GAP-43) and synaptic (synaptophysin and synapsin I) proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by K252a (trkA inhibitor). CBD did not increase the expression of NGF, but protected against its decrease induced by MPP(+), probably by an indirect mechanism. We also evaluated the neuritogenesis in SH-SY5Y cells, which do not express trkA receptors. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors. This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Our findings suggest that CBD has a neurorestorative potential independent of NGF that might contribute to its neuroprotection against MPP(+), a neurotoxin relevant to Parkinson's disease.

Plastic and Neuroprotective Mechanisms Involved in the Therapeutic Effects of Cannabidiol in Psychiatric Disorders

“…CBD normalized synaptophysin levels in rats submitted to a brain damage by iron overload (da Silva et al, 2014) and produced a neuritogenic effect in PC12 cells, increasing the expression of synaptophysin and synapsin I. These effects were inhibited by a TrkA antagonist (Santos et al, 2015). In addition, CBD can modulate intracellular pathways directly related to synaptic remodeling, such as Erk1/2 and Akt, in different types of cancer cell lines (McAllister et al, 2011; Solinas et al, 2013).…”

Potencial neuroprotetor, antioxidante e anti-inflamatório do Canabidiol: relevância e perspectivas para o tratamento de doenças neurodegenerativas.

“…Os resultados sugerem que o ferro afetou a dinâmica mitocondrial e desencadeou perda sináptica e morte celular por apoptose, o que foi revertido pelo tratamento com CBD, indicando que este exerceu atividade neuroprotetora e pode ser um importante agente terapêutico em casos de degeneração neuronal causada pelo acumulo de ferro, como é característico na Doença de Parkinson e Alzheimer. Santos et al (2015) o CBD exerceu efeitos benéficos quando administrado em modelos experimentais de doenças neurodegenerativas. Esses efeitos foram primeiramente pautados na eficácia do CBD em reduzir a presença de ROS e iNOS, mediando processos antioxidante e neuroprotetores e também em sua capacidade de inibição das enzimas associadas à apoptose, como a caspase 3 a e caspase 9, minimizando a perda neuronal e um possível declínio cognitivo associado a perda sináptica.…”

Biological bases for a possible effect of cannabidiol in Parkinson’s disease

“…These neuroprotective effects depended on the activation of tropomyosin receptor kinase A (TrkA) receptors. 97 CBD also protected SH-SY5Y cells against LPS-and b-amyloidinduced decreases in cell viability, while increasing the viability of SH-SY5Y cells incubated with conditioned media derived from microglia previously activated with LPS. 98 In another study, CBD blunted ATP-induced increases in intracellular calcium and LPS-evoked nitrite generation in both N13 microglial cells and rat primary microglia.…”