Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on b-amyloid-induced toxicity in PC12 cells, Teresa Iuvone et al., 2004

Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on b-amyloid-induced toxicity in PC12 cells

Teresa Iuvone, Giuseppe Esposito, Ramona Esposito, Rita Santamaria, Massimo Di Rosa and
Angelo A. Izzo

Journal of Neurochemistry, 2004, 89, 134–141




Alzheimer’s disease is widely held to be associated with oxidative stress due, in part, to the membrane action of b-amyloid peptide aggregates. Here, we studied the effect of cannabidiol, a major non-psychoactive component of the marijuana plant (Cannabis sativa) on b-amyloid peptide-induced toxicity
in cultured rat pheocromocytoma PC12 cells. Following exposure of cells to b-amyloid peptide (1 lg/mL), a marked reduction in cell survival was observed. This effect was associated with increased reactive oxygen species (ROS) production and lipid peroxidation, as well as caspase 3 (a key enzyme in the apoptosis cell-signalling cascade) appearance, DNA fragmentation and increased intracellular calcium. Treatment of the cells with cannabidiol (10)7)10)4 M) prior to b-amyloid peptide exposure significantly elevated cell survival while it decreased ROS production, lipid peroxidation, caspase 3 levels, DNA fragmentation and intracellular calcium. Our results indicate that cannabidiol exerts a combination
of neuroprotective, anti-oxidative and anti-apoptotic effects against b-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection.

Keywords : Alzheimer’s disease, apoptosis, b-amyloid, cannabidiol, cannabinoid, neuroprotection.


Alzheimer’s disease (AD) is the most common age-related neurodegenerative disorder (Koo et al. 1999). Regional neuronal degeneration, synaptic loss, presence of neurofibrillary angles (NFTs) (Terry 1963) and senile plaques (Braak and Braak 1997) are specific hallmarks of this disease. While NFTs are the result of disposition of hyper-phosphorylated tau protein (Lee et al. 1991), senile plaques are complex
extracellular lesions composed of a core of b-amyloid (Ab) aggregates, surrounded by activated astrocytes, and dystrophic neuritis (Itagaki et al. 1989; Cotman et al. 1996).

Excessive accumulation of Ab peptide has been proposed as a pivotal event in the pathogenesis of AD, although the precise mechanism by which Ab induces neuronal death is still unknown (Hensley et al. 1994; Troy et al. 2001). Proposed mechanisms include production of oxygen free radicals (Behl et al. 1994), modification of cytosolic calcium homeostasis (Mattson 1992; Ueda et al. 1997), the Wnt pathway and activation of nuclear factor-kB (Green and Peers 2002; Caricasole et al. 2003). The cysteine proteases, known as caspases, are essential mediators of many of the pathways involved in executing the apoptotic programme following Ab accumulation (Gervais et al. 1999). Caspasemediated apoptosis can be modulated by several agents, including antioxidants (Behl et al. 1994), calcium channel blockers (Weiss et al. 1994) and growth factors (Mattson et al. 1993).

Cannabinoids are a group of C21 compounds occurring in the glandular hairs of Cannabis sativa (Indian hemp) and consequently in hashish and marijuana, the well known of abuse (Samuelsson 1999; Nocerino et al. 2000). The most important representative cannabinoid is D9-tetrahydrocannabinol
(D9-THC), which has psychoactive properties depending upon the interaction with the cannabinoid CB1
receptors within the brain (Pertwee 1997). Good quality hashish contains 4–10% and marijuana 0.1–2.7% D9-THC (Samuelsson 1999). Cannabidiol, the main component of the glandular hairs (up to 15%), is a non-psychoactive cannabinoid; it exerts a plethora of pharmacological effects, including anti convulsive, sedative, hypnotic, anti-psychotic, anti-nausea and anti-inflammatory actions (Mechoulam et al. 2002). Cannabidiol is a potent antioxidant compound and it has been recently proposed to have a neuroprotective role during ischemic damage (Hampson et al. 1998, 2000).

The aim of the present study is to evaluate the possible neuroprotective effect of cannabidiol on b-amyloid-induced neurotoxicity. For this purpose we evaluated the effect of cannabidiol on cell viability, reactive oxygen species (ROS) formation and membrane lipoperoxidation, as well as neuronal apoptosis in cultured rat pheochromocytoma PC12 cells exposed to Ab.