Gaining Control Therapeutic Intervention in CNS Inflammation

Microglia as Therapeutic Target

Very recently, Heppner and colleagues directly targeted microglial activities using CD11b-HSVTK transgenic mice and bone marrow chimeras in which a specific lack of microglial activation was achieved (Heppner et al. 2005). Using this approach, inflammatory CNS lesions were repressed, resulting in a marked reduction of the severity of the animal model of MS. Furthermore, the authors demonstrated that microglial cells are crucial for the development of EAE, presumably mediated by the release of cytokines and chemokines as well as reactive oxygen species, as studied in organotypic hippocampal slice cultures. Future studies should examine whether classical neurodegenerative diseases may also benefit from a specific microglia targeting strategy, and how this approach can be translated into clinical application. There are already several therapeutic agents in clinical use or development, which target microglial activities, among other effects. In particular, some non-steroidal anti-inflammatory drugs (NSAID) seem to have beneficial effects in neurodegenerative diseases such as Alzeimer's (McGeer and McGeer 2001). Recently, the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone resulted in a reduction in number of activated microglia with reduced expression of the proinflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS), and a reduction of amyloid deposits in the hippocampus and cortex of an Alzheimer model (Heneka et al. 2005). Minocy-cline, which is known to have neuroprotective properties, was recently shown to reduce the release of cytotoxins from activated microglia (Krady et al. 2005). However, anti-inflammatory approaches to blocking microglial activation or microglial effector mechanisms are likely non-specific, indiscriminate strategies. Moreover, they do not simply reduce inflammatory damage on the one hand, but they also run the risk of inhibiting protective immunity on the other hand. Therefore, from the clinical point of view, the identification and therapeutic support of anti-inflammatory negative feedback loops might be the better choice because these are only active after immune activation and therefore harbour a low risk of undesired overinhibition of immune reactions. This means that the therapeutic support of endogenous negative regulatory feedback-loops might be a highly efficient and clinically safe strategy of neuroprotective intervention. Here, the endocannabinoid system, a major negative regulatory system in the nervous and immune system of the CNS, may represent one promising new therapeutic target in the treatment of acute and chronic neurodegenerative diseases.

Cannabinoid System as Therapeutic Target

Because of its possible involvement in immune control and neuroprotection, cannabinoids are discussed intensively for treatment of inflammatory disease (Croxford et al. 2005) and moreover as an interesting option in the treatment of neuroinflammation (Correa et al. 2005). Recently we found that the endocannabinoid system is highly activated in patients with MS and identified the release of AEA by inflamed CNS tissue as a new mechanism of neuro-immune-communication during CNS injury, which controls and limits immune response and protect neurons (Eljaschewitsch et al. 2006). A previous study reported elevated endocannabinoid levels in autoimmune en-cephalomyelitis (EAE), the experimental model of MS, in association with spasticity due to spinal cord pathology (Baker et al. 2001). In EAE, CB1 receptor stimulation ameliorated spasticity and tremor (Baker et al. 2000, 2004, Arevalo-Martin et al. 2003) and reduced neuronal damage and axonal loss (Pryce et al. 2003), whereas the CB1 receptor antagonist Rimonabant® transiently worsens signs (Baker et al. 2000, 2001, 2004). Evidence for the participation of endocannabinoid signalling in human MS came from clinical observations that a previously undiagnosed MS exacerbated by Rimonabant® in a person being treated for obesity (van Oosten et al. 2004).

Treatment of MS with the cannabis extracts (Cannador) lowered the frequency of spasms and improved the mobility in a randomized double-blind crossover study (Vaney et al. 2004). Bladder dysfunction has been improved by THC and Sativex in a small-scale open-label study (Brady et al. 2004), as well as patient perceptions of pain and spasticity (Pertwee et al. 2002, Svend-sen et al. 2004). On the other hand, no positive effects on spasticity has been reported in patients treated with oral Marinol or Cannador in a blinded trial (Killestein et al. 2002).

In the largest clinical study about the use of cannabinoids for treating symptoms related to MS (CAMS), where 667 people were orally administered over a 15 week period with capsules of THC (Marinol®), capsules of cannabis extract Cannador® or placebo capsules, a subjective improvement of specific symptoms (pain, spasticity, sleep disturbance, walking time), but no effect on spasticity and tremor has been reported (Zajicek et al. 2003). However, in a one-year follow-up of the CAMS study, overall objective improvements on both spasticity (Ashworth Scale) and general disability indices have been found (Zajicek et al. 2004). The results of the long-term CAMS study are particularly encouraging because they indicate that cannabis not only relieves symptoms but also is potentially neuroprotective and involved in synaptic plasticity; this should be investigated further.

In conclusion, clinical trials ended with both positive and negative results (Pertwee et al. 2002), which could be the consequence of several problems: First, exogenous cannabinoids might interfere locally with endogenous cannabinoids, since they are only partial agonists on cannabinoid receptors. Second, oral delivery of cannabinouid drugs produces a slow and low increase in plasma THC levels (Huestis et al. 1992, Grotenhermen 2003, Wall et al. 1983, Ohlsson et al. 1980, Timpone et al. 1997), whereas a correlation of optimal plasma THC levels with symptom improvement is missing from many studies. Third, the Ashworth scale to measure spasticity might not be sufficiently sensitive to measure small but clinically beneficial effects (Shakespeare et al. 2003). In conclusion, improvements in trial design and outcome measurements are important in clarifying the situation. To overcome problems in the oral delivery of cannabinoids, the sub-lingual spray Sativex® has been developed improvement, which demonstrated beneficial effects on spasticity in patient-assessed scores (visual analogue scale), but no improvement as measured by the Ashworth scale in a placebo-controlled study in 160 MS patients (Wade et al. 2004).

In conclusion, the endocannabinoid system represents a local messenger system within and between the nervous and immune systems, which is apparently involved in learning and memory, emotions, pain processing, regulation of motor functions, control of immune activation and neuroprotection. Therefore, elucidating the integration of the endocannabinoid system in intra- and intercellular signalling networks and their function during physiology and pathophysiology might open new avenues of therapeutic interventions in the future. A successful therapeutic strategy has to maintain or restore the well-controlled and finely-tuned balance ofimmune reactions, and to protect neurons from inflammatory and non-inflammatory damage.

Acknowledgements Minor parts of this chapter (Fig. 1) have also been published by the authors in Signal Transduction 1-2, 19-27 (2005); these sections appear with kind permission of Wiley VCH. We thank Mr. Andrew Mason for his excellent assistance.

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