The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-ß and in the cortex of aged rats.

Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons. We also provide evidence that although Aß(1-42) increases expression of the endogenous inhibitor of Notch-1, numb (Nb), this can be prevented by AEA and 2-arachidonoylglycerol. Interestingly, AEA up-regulated Nct expression, a component of γ-secretase, and this was found to play a crucial role in the enhanced Notch-1 signaling mediated by AEA. The stimulatory effects of AEA on Notch-1 signaling persisted in the presence of Aß(1-42). AEA was found to induce a preferential processing of Notch-1 over amyloid precursor protein to generate Aß(1-40). Aging, a natural process of neurodegeneration, was associated with a reduction in Notch-1 signaling in rat cortex and hippocampus, and this was restored with chronic treatment with URB 597. In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD.

The fatty acid amide hydrolase inhibitor URB597 exerts anti-inflammatory effects in hippocampus of aged rats and restores an age-related deficit in long-term potentiation.

BACKGROUND: Several factors contribute to the deterioration in synaptic plasticity which accompanies age and one of these is neuroinflammation. This is characterized by increased microglial activation associated with increased production of proinflammatory cytokines like interleukin-1ß (IL-1ß). In aged rats these neuroinflammatory changes are associated with a decreased ability of animals to sustain long-term potentiation (LTP) in the dentate gyrus. Importantly, treatment of aged rats with agents which possess anti-inflammatory properties to decrease microglial activation, improves LTP. It is known that endocannabinoids, such as anandamide (AEA), have anti-inflammatory properties and therefore have the potential to decrease the age-related microglial activation. However, endocannabinoids are extremely labile and are hydrolyzed quickly after production. Here we investigated the possibility that inhibiting the degradation of endocannabinoids with the fatty acid amide hydrolase (FAAH) inhibitor, URB597, could ameliorate age-related increases in microglial activation and the associated decrease in LTP. METHODS: Young and aged rats received subcutaneous injections of the FAAH inhibitor URB597 every second day and controls which received subcutaneous injections of 30% DMSO-saline every second day for 28 days. Long-term potentiation was recorded on day 28 and the animals were sacrificed. Brain tissue was analyzed for markers of microglial activation by PCR and for levels of endocannabinoids by liquid chromatography coupled to tandem mass spectrometry. RESULTS: The data indicate that expression of markers of microglial activation, MHCII, and CD68 mRNA, were increased in the hippocampus of aged, compared with young, rats and that these changes were associated with increased expression of the proinflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor-α (TNFα) which were attenuated by treatment with URB597. Coupled with these changes, we observed an age-related decrease in LTP in the dentate gyrus which was partially restored in URB597-treated aged rats. The data suggest that enhancement of levels of endocannabinoids in the brain by URB597 has beneficial effects on synaptic function, perhaps by modulating microglial activation.

Endocannabinoids prevent ß-amyloid-mediated lysosomal destabilization in cultured neurons.

Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by ß-amyloid (Aß) is thus important for the development of therapeutic strategies that can thwart Aß toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by Aß. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against Aß-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the Aß-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against Aß toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection.

Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: a role for AKT and hypoxia-inducible factor (HIF)-1alpha.

Mesenchymal stem cells (MSCs) are multipotent cells capable of developing along the chondrogenic, osteogenic and adipogenic lineages. As such, they have received interest as a potential cell source for tissue engineering strategies. Cartilage is an avascular tissue and thus resides in a microenvironment with reduced oxygen tension. The aim of this study was to examine the effect of a low oxygen environment on MSC differentiation along the chondrogenic route. In MSCs exposed to chondrogenic growth factors, transforming growth factor-beta and dexamethasone, in a hypoxic environment (2% oxygen), the induction of collagen II expression and proteoglygan deposition was significantly greater than that observed when cells were exposed to the chondrogenic growth factors under normoxic (20% oxygen) conditions. The transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha), is a crucial mediator of the cellular response to hypoxia. Following exposure of MSCs to hypoxia (2% oxygen), HIF-1alpha translocated from the cytosol to the nucleus and bound to its target DNA consensus sequence. Similarly, hypoxia evoked an increase in phosphorylation of both AKT and p38 mitogen activated protein kinase, upstream of HIF-1alpha activation. Furthermore, the PI3 kinase/AKT inhibitor, LY294002, and p38 inhibitor, SB 203580, prevented the hypoxia-mediated stabilisation of HIF-1alpha. To assess the role of HIF-1alpha in the hypoxia-induced increase in chondrogenesis, we employed an siRNA knockdown approach. In cells exposed to HIF-1alpha siRNA, the hypoxia-induced enhancement of chondrogenesis, as evidenced by upregulation of collagen II, sox-9 and proteoglycan deposition, was absent. This provides evidence for HIF-1alpha being a key mediator of the beneficial effect of a low oxygen environment on chondrogenesis.

A role for p53 in the regulation of lysosomal permeability by delta 9-tetrahydrocannabinol in rat cortical neurones: implications for neurodegeneration.

The psychoactive ingredient of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), can evoke apoptosis in cultured cortical neurones. Whilst the intracellular mechanisms responsible for this apoptotic pathway remain to be fully elucidated, we have recently identified a role for the CB1 type of cannabinoid (CB) receptor and the tumour suppressor protein, p53. In the current study, we demonstrate the Delta9-THC promotes a significant increase in lysosomal permeability in a dose- and time-dependent manner. The increase in lysosomal permeability was blocked by the CB1 receptor antagonist, AM251. Delta9-THC increased the localization of phospho-p53Ser15 at the lysosome and stimulated the release of the lysosomal cathepsin enzyme, cathepsin-D, into the cytosol. The p53 inhibitor, pifithrin-alpha and small interfering RNA-mediated knockdown of p53 prevented the Delta9-THC-mediated increase in lysosomal permeability. Furthermore, the Delta9-THC -mediated induction of apoptosis was abrogated by a cell-permeable cathepsin-D inhibitor (10 microM). Thus, the study demonstrates that Delta9-THC impacts on the lysosomal system, via p53, to evoke lysosomal instability as an early event in the apoptotic cascade. This provides evidence for a novel link between the CB1 receptor and the lysosomal branch of the apoptotic pathway which is crucial in regulating neuronal viability following exposure to Delta9-THC.

A comparison of the involvement of p38, ERK1/2 and PI3K in growth factor-induced chondrogenic differentiation of mesenchymal stem cells.

Adult mesenchymal stem cells (MSCs) are under investigation as an alternative cell source for the engineering of cartilage tissue in three-dimensional (3D) scaffolds. However, little is known about the intracellular mechanisms involved in the chondrogenic differentiation of MSCs. This study investigated the signaling pathways evoked by TGF-beta1 and IGF-1 that mediated chondrogenic differentiation in adult rat bone-marrow derived MSCs in (i) monolayer on plastic and (ii) a 3D collagen-GAG scaffold. The data demonstrated involvement of the p38 pathway, but not ERK1/2 or PI3K in TGF-beta1-induced chondrogenic differentiation in monolayer. Similarly, when the MSCs were seeded onto a collagen-GAG scaffold and treated with TGF-beta1, the chondrogenic differentiation was dependent upon p38. In contrast, IGF-1-induced chondrogenic differentiation in monolayer involved p38, ERK1/2, as well as PI3K. The phosphorylation of Akt occurred downstream of PI3K and phospho-Akt was found to accumulate in the nucleus of IGF-1-treated cells. When MSCs were seeded onto the collagen-GAG scaffold and exposed to IGF-1, PI3K was required for chondrogenesis. These findings highlight the respective and differential involvement of p38, ERK1/2 and PI3K in growth factor-induced chondrogenesis of MSCs and demonstrates that intracellular signaling pathways are similar when differentiation is stimulated in a 2D or 3D environment.

Involvement of stretch-activated ion channels in strain-regulated glycosaminoglycan synthesis in mesenchymal stem cell-seeded 3D scaffolds.

The objective of this study was to determine if cyclic tensile strain would regulate the rate of glycosaminoglycan synthesis via stretch-activated ion channels in adult mesenchymal stem cells seeded in a collagen type I-glycosaminoglycan scaffold and treated with TGF-beta1. The application of 10% cyclic tensile loading at 1Hz for 7 days significantly increased the rate of glycosaminoglycan synthesis, as assessed using [(35)S] sulphate incorporation. This increase was attenuated in the presence of a stretch-activated ion channel inhibitor (10microM gadolinium chloride) demonstrating the involvement, in part, of these ion channels in the mechanotransduction pathway that couples cyclic tensile loading to matrix synthesis.

A comparison of the apoptotic effect of Delta(9)-tetrahydrocannabinol in the neonatal and adult rat cerebral cortex.

The maternal use of cannabis during pregnancy results in a number of cognitive deficits in the offspring that persist into adulthood. The endocannabinoid system has a role to play in neurodevelopmental processes such as neurogenesis, migration and synaptogenesis. However, exposure to phytocannabinoids, such as Delta(9)-tetrahydrocannabinol, during gestation may interfere with these events to cause abnormal patterns of neuronal wiring and subsequent cognitive impairments. Aberrant cell death evoked by Delta(9)-tetrahydrocannabinol may also contribute to cognitive deficits and in cultured neurones Delta(9)-tetrahydrocannabinol induces apoptosis via the CB(1) cannabinoid receptor. In this study we report that Delta(9)-tetrahydrocannabinol (5-50 microM) activates the stress-activated protein kinase, c-jun N-terminal kinase, and the pro-apoptotic protease, caspase-3, in in vitro cerebral cortical slices obtained from the neonatal rat brain. The proclivity of Delta(9)-tetrahydrocannabinol to impact on these pro-apoptotic signalling molecules was not observed in in vitro cortical slices obtained from the adult rat brain. In vivo, subcutaneous administration of Delta(9)-tetrahydrocannabinol (1-30 mg/kg) activated c-jun N-terminal kinase, caspase-3 and cathepsin-D, and induced DNA fragmentation in the cerebral cortex of neonatal rats. In contrast, in vivo administration of Delta(9)-tetrahydrocannabinol to adult rats was not associated with the apoptotic pathway in the cerebral cortex. The data provide evidence which supports the hypothesis that the neonatal rat brain is more vulnerable to the neurotoxic influence of Delta(9)-tetrahydrocannabinol, suggesting that the cognitive deficits that are observed in humans exposed to marijuana during gestation may be due, in part, to abnormal engagement of the apoptotic cascade during brain development.

The tumour suppressor protein, p53, is involved in the activation of the apoptotic cascade by Delta9-tetrahydrocannabinol in cultured cortical neurons.

Cannabis is the most commonly used illegal drug of abuse in Western society. Delta(9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana, regulates a variety of neuronal processes including neurotransmitter release and synaptic transmission. An increasing body of evidence suggests that cannabinoids play a key role in the regulation of neuronal viability. In cortical neurons tetrahydrocannabinol has a neurodegenerative effect, the mechanisms of which are poorly understood, but involve the cannabinoid receptor subtype, CB(1). In this study we report that tetrahydrocannabinol (5 muM) evokes a rapid phosphorylation, and thus activation, of the tumour suppressor protein, p53, in a manner involving the cannabinoid CB(1) receptor, and the stress-activated protein kinase, c-jun N-terminal kinase, in cultured cortical neurons. Tetrahydrocannabinol increased expression of the p53-transcriptional target, Bax and promoted Bcl phosphorylation. These events were abolished by the p53 inhibitor, pifithrin-alpha (100 nM). The tetrahydrocannabinol-induced activation of the pro-apoptotic cysteine protease, caspase-3, and DNA fragmentation was also blocked by pifithrin-alpha. A siRNA knockdown of p53 further verified the role of p53 in tetrahydrocannabinol-induced apoptosis. This study demonstrates a novel cannabinoid signalling pathway involving p53 that culminates in neuronal apoptosis.

Analysis of the Impact of CD200 on Phagocytosis.

One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is observed with age, in models of Alzheimer's and Parkinson's disease as well as in the human diseases. There is evidence of increased microglial activation in CD200-deficient mice, and isolated microglia prepared from these mice are more reactive to inflammatory stimuli like Toll-like receptor 2 and 4 agonists, and interferon-γ. Here, we examined the impact of CD200 deficiency on amyloid-ß (Aß)-induced changes in microglia and report, perhaps unexpectedly, that the effect of Aß was attenuated in microglia prepared from CD200-deficient mice. The evidence indicates that this is a consequence of increased phagocytosis, associated with increased lysosomal activity in CD200-deficient microglia. The data suggest that mTOR-related signalling is decreased in these cells and that inhibiting mTOR by rapamycin increases phagocytosis. Thus, while the findings to date have emphasized the anti-inflammatory effects of CD200-CD200R interaction, the present evidence indicates a previously unreported impact on lysosomal function.

A collagen-glycosaminoglycan scaffold supports adult rat mesenchymal stem cell differentiation along osteogenic and chondrogenic routes.

Adult mesenchymal stem cells have the proclivity to differentiate along multiple lineages giving rise to new bone, cartilage, muscle, or fat. Collagen, a normal constituent of bone, provides strength and structural stability and is therefore a potential candidate for use as a substrate on which to engineer bone and cartilage from their respective mesenchymal-derived precursors. In this study, a collagen- glycosaminoglycan scaffold was used to provide a suitable three-dimensional (3-D) environment on which to culture adult rat mesenchymal stem cells and induce differentiation along the osteogenic and chondrogenic lineages. The results demonstrate that adult rat mesenchymal stem cells can undergo osteogenesis when grown on the collagen-glycosaminoglycan scaffold and stimulated with osteogenic factors (dexamethasone, ascorbic acid, beta-glycerophosphate), as evaluated by the temporal induction of the bone-specific proteins, collagen I and osteocalcin, and subsequent matrix mineralization. The osteogenic factors were coupled to activation of the extracellular-regulated protein kinase (ERK), and this kinase was found to play a role in the osteogenic process. As well as supporting osteogenesis, when the cell-seeded scaffold was exposed to chondrogenic factors (dexamethasone and TGF-1beta), collagen II immunoreactivity was increased, providing evidence that the scaffold can also provide a suitable 3-D environment that supports chondrogenesis.

Aging enhances the vulnerability of mesenchymal stromal cells to uniaxial tensile strain-induced apoptosis.

Mechanical priming can be employed in tissue engineering strategies to control the fate and differentiation pattern of mesenchymal stromal cells. This is relevant to regenerative medicine whereby mechanical cues can promote the regeneration of a specific tissue type from mesenchymal precursors. The ability of cells to respond to mechanical forces is dependent upon mechanotransduction pathways that involve membrane-associated proteins, such as integrins. During the aging process changes in the mechanotransduction machinery may influence how cells from aged individuals respond to mechanical priming. In this study mesenchymal stromal cells were prepared from young adult and aged rats and exposed to uniaxial tensile strain at 5% and 10% for 3 days, or 2.5% for 7 days. Application of 5% tensile strain had no impact on cell viability. In contrast, application of 10% tensile strain evoked apoptosis and the strain-induced apoptosis was significantly higher in the mesenchymal stromal cells prepared from the aged rats. In parallel to the age-related difference in cellular responsiveness to strain, an age-related decrease in expression of α2 integrin and actin, and enhanced lipid peroxidation was observed. This study demonstrates that mesenchymal stem cells from aged animals have an altered membrane environment, are more vulnerable to the pro-apoptotic effects of 10% tensile strain and less responsive to the pro-osteogenic effects of 2.5% tensile strain. Thus, it is essential to consider how aged cells respond to mechanical stimuli in order to identify optimal mechanical priming strategies that minimise cell loss, particularly if this approach is to be applied to an aged population.

The Emerging Role of the Cannabinoid Receptor Family in Peripheral and Neuro-immune Interactions.

The classical endogenous cannabinoid (CB) system is composed of the endocannabinoid signalling molecules, 2-arachidonoyl glycerol (2-AG) and anandamide (AEA) and their G-protein coupled receptors (GPCR), CB1 and CB2 which together constitutes the endocannabinoid system (ECS). However, putative, novel lipid-sensing CB receptors have recently been identified, including the orphan GPR55 and GPR18 receptors that are regulated by cannabinoid-like molecules and interact with CB system. CB receptors and associated orphan GPCRs are expressed at high levels in the immune and/or central nervous systems (CNS) and regulate a number of neurophysiological processes, including key events involved in neuroinflammation. As such, these receptors have been identified as emerging therapeutic targets for a number of brain disorders in which neuroinflammation is a key feature, including multiple sclerosis (MS) and Alzheimer's disease (AD). This review will consider the role of the wider cannabinoid receptor superfamily in mediating immune function with a focus on the immune processes that contribute to neuroinflammatory conditions.

Effect of membrane stiffness and cytoskeletal element density on mechanical stimuli within cells: an analysis of the consequences of ageing in cells.

A finite element model of a single cell was created and used to compute the biophysical stimuli generated within a cell under mechanical loading. Major cellular components were incorporated in the model: the membrane, cytoplasm, nucleus, microtubules, actin filaments, intermediate filaments, nuclear lamina and chromatin. The model used multiple sets of tensegrity structures. Viscoelastic properties were assigned to the continuum components. To corroborate the model, a simulation of atomic force microscopy indentation was performed and results showed a force/indentation simulation with the range of experimental results. A parametric analysis of both increasing membrane stiffness (thereby modelling membrane peroxidation with age) and decreasing density of cytoskeletal elements (thereby modelling reduced actin density with age) was performed. Comparing normal and aged cells under indentation predicts that aged cells have a lower membrane area subjected to high strain as compared with young cells, but the difference, surprisingly, is very small and may not be measurable experimentally. Ageing is predicted to have a more significant effect on strain deep in the nucleus. These results show that computation of biophysical stimuli within cells are achievable with single-cell computational models; correspondence between computed and measured force/displacement behaviours provides a high-level validation of the model. Regarding the effect of ageing, the models suggest only small, although possibly physiologically significant, differences in internal biophysical stimuli between normal and aged cells.

Evidence of a protective effect of phosphatidylserine-containing liposomes on lipopolysaccharide-induced impairment of long-term potentiation in the rat hippocampus.

Lipopolysaccharide (LPS) has a negative impact on long-term potentiation (LTP) in the rat hippocampus, which has been correlated with increased concentration of interleukin-1 beta (IL-1 beta) and activation of p38 and c-Jun N-terminal kinase (JNK). It has been documented that phosphatidylserine (PS)-containing liposomes induce anti-inflammatory signals and we report that pre-treatment of rats with PS liposomes prevented these LPS-induced effects while also inhibiting microglial activation. We also observed increased concentration of the anti-inflammatory cytokine interleukin-10 (IL-10), whose intracerebroventricular injection administration mimicked the effects of PS liposomes on LTP. This suggests that administration of PS liposomes protects against the deleterious effects of LPS possibly through generation of the anti-inflammatory cytokine IL-10.

Tetrahydrocannabinol-induced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons.

Delta9-Tetrahydrocannabinol (THC), the main psychoactive ingredient of marijuana, induces apoptosis in cultured cortical neurons. THC exerts its apoptotic effects in cortical neurons by binding to the CB1 cannabinoid receptor. The CB1 receptor has been shown to couple to the stress-activated protein kinase, c-Jun N-terminal kinase (JNK). However, the involvement of specific JNK isoforms in the neurotoxic properties of THC remains to be established. The present study involved treatment of rat cultured cortical neurons with THC (0.005-50 microM), and combinations of THC with the CB1 receptor antagonist, AM 251 (10 microM) and pertussis toxin (PTX; 200 ng ml-1). Antisense oligonucleotides (AS) were used to deplete neurons of JNK1 and JNK2 in order to elucidate their respective roles in THC signalling. Here we report that THC induces the activation of JNK via the CB1 receptor and its associated G-protein, Gi/o. Treatment of cultured cortical neurons with THC resulted in a differential timeframe of activation of the JNK1 and JNK2 isoforms. Use of specific JNK1 and JNK2 AS identified activation of caspase-3 and DNA fragmentation as downstream consequences of JNK1 and JNK2 activation. The results from this study demonstrate that activation of the CB1 receptor induces JNK and caspase-3 activation, an increase in Bax expression and DNA fragmentation. The data demonstrate that the activation of both JNK1 and JNK2 isoforms is central to the THC-induced activation of the apoptotic pathway in cortical neurons.

The cannabinoid receptor type 1 is essential for mesenchymal stem cell survival and differentiation: implications for bone health.

Significant loss of bone due to trauma, underlying metabolic disease, or lack of repair due to old age surpasses the body's endogenous bone repair mechanisms. Mesenchymal stem cells (MSCs) are adult stem cells which may represent an ideal cell type for use in cell-based tissue engineered bone regeneration strategies. The body's endocannabinoid system has been identified as a central regulator of bone metabolism. The aim of the study was to elucidate the role of the cannabinoid receptor type 1 in the differentiation and survival of MSCs. We show that the cannabinoid receptor type 1 has a prosurvival function during acute cell stress. Additionally, we show that the phytocannabinoid, Δ(9)-Tetrahydrocannabinol, has a negative impact on MSC survival and osteogenesis. Overall, these results show the potential for the modulation of the cannabinoid system in cell-based tissue engineered bone regeneration strategies whilst highlighting cannabis use as a potential cause for concern in the management of orthopaedic patients.

The multiplicity of action of cannabinoids: implications for treating neurodegeneration.

The cannabinoid (CB) system is widespread in the central nervous system and is crucial for controlling a range of neurophysiological processes such as pain, appetite, and cognition. The endogenous CB molecules, anandamide, and 2-arachidonoyl glycerol, interact with the G-protein coupled CB receptors, CB(1) and CB(2). These receptors are also targets for the phytocannabinoids isolated from the cannabis plant and synthetic CB receptor ligands. The CB system is emerging as a key regulator of neuronal cell fate and is capable of conferring neuroprotection by the direct engagement of prosurvival pathways and the control of neurogenesis. Many neurological conditions feature a neurodegenerative component that is associated with excitotoxicity, oxidative stress, and neuroinflammation, and certain CB molecules have been demonstrated to inhibit these events to halt the progression of neurodegeneration. Such properties are attractive in the development of new strategies to treat neurodegenerative conditions of diverse etiology, such as Alzheimer's disease, multiple sclerosis, and cerebral ischemia. This article will discuss the experimental and clinical evidence supporting a potential role for CB-based therapies in the treatment of certain neurological diseases that feature a neurodegenerative component.

Phytocannabinoids, CNS cells and development: a dead issue?

ISSUES: Marijuana and hashish consist of at least 66 distinctive plant-derived (phyto-) cannabinoid compounds, with tetrahydrocannabinoids proving the most effective phytocannabinoid psychotropically. Despite the known pharmacological effects of phytocannabinoids, their role in controlling the cell survival/death decision in cells of the CNS continues to be unravelled. APPROACH: In this review, we examine the influence of phytocannabinoids on neural cell fate, with particular emphasis on how the time of marijuana exposure (neonatal vs. pubertal vs. adult) might influence the neurotoxic activities of phytocannabinoid compounds. KEY FINDINGS: Evidence in the literature indicates that exposure to phytocannabinoids during the prenatal period, in addition to the adolescent period, can alter the temporally ordered sequence of events that occur during neurotransmitter development, in addition to negatively impacting neural cell survival and maturation. Regarding the effect of marijuana consumption on brain composition in adults the evidence is contradictory. IMPLICATIONS: Exposure to marijuana during pregnancy might impact negatively on brain structure in the first years of postnatal life. Furthermore, early-onset (before age 17) marijuana use might also have damaging effects on brain composition. CONCLUSION: The neonatal and immature CNS is more susceptible to phytocannabinoid damage. In the adult CNS the data are conflicting and the continued development of methods to assess whether marijuana consumption results in brain atrophy or morphometric changes will determine if structural changes are occurring.