The conditioning lesion effect
Indeed it is well established that the inability to regenerate is due external inhibitors that act ultimately on the cytoskeleton and thus lead to the annulment of the neuronal growth ability which was yet presumably preserved before the lesion.
However this growth status depends in a first instance on the neurons themselves. For example, as emphasized by Li and Raisman unfavorable environment of the adult CNS does not prevent embryonic, when transplanted into rat adult spinal cord, to extend long-distance axons (Li &
Raisman 1993). The embryonic neurons have thus a different growth capacity from their adult counterparts and it is their intrinsic state which dictates their response to the inhibitory factors of the environment. Very importantly, Neumann and Woolf have shown dorsal branch of DRG neurons displays a complete regeneration (in the spinal cord which an inhibitory environment) if one or two weeks before the lesion the peripheral branch of the DRG was lesioned (Figure 17). This experimental paradigm named “conditioning lesion effect” shows that the intrinsic growth status of the neurons is a key factor for central nervous regeneration (Neumann & Woolf 1999).
Figure17: Principle of the conditioning lesion paradigm.
A lesion to the peripheral branch (1) of DRG neurons prior the lesion of the central branch (2) blocks the myelin–
related inhibition.
This technique have been and are still used to dissect-out what are the molecular factors that determine and are susceptible to increase the intrinsic growth status.
Cai et al reported that if, before the lesion of the central branch (without a lesion of the peripheral), neurons were prior (process known as “priming”) exposed to neutrophins the inhibitory effect of myelinic inhibitors is blocked (Cai et al. 1999). This effect (dorsal column regeneration) is mimicked if the neurons are injected with cAMP before the lesion of the dorsal branch and was revealed to be, in the day following the lesion, to be PKA dependent, the PKA inactivating the Rho signaling. Seven days following the lesion, the dorsal column grows better in myelin but this growth is now PKA independent (Sandvig et al. 2004, Qiu et al. 2000, Filbin 2003, Ruff et al.
2008). Probably the blockade of the inhibition is accounted by an indirect effect of the PKA that initiates the transcription of genes (via CREB) such as small proline-rich repeat protein called Sprr1a which is known to be associated to F-actin in the growth cone and to promote axonal outgrowth (Bonilla et al. 2002).
Figure 18: Signalings pathways of myelinic inhibitors versus neurotrophin/cAMP on cytoskeleton (Filbin 2003) .
Epilogue
The glial inhibition is not the only factor that plays a key role in nervous regeneration.
In first instance, CNS subsequent regeneration/sprouting is obviously and basically determined by the severity, the nature of the insult as well as the cellular reactions take place a few after an injury.
The CNS inflammation is probably the most encountered of these reactions.
However the rapid release of proinflammatory cytokines constitutes the initial and the common feature of main of the CNS insults. They are the Interleukin-1 (IL-1), Tumor necrosis-alpha (TNFα) and the Interleukin-6 (IL-6). These molecules mediate secondary other cascades of cellular reactions and signal transductions whose the final outcome can be redundant but also opposite (beneficial versus detrimental). This characteristic of action is often imaged by the specialists as a
“double edge sword”. That illustrates why we cannot qualify the neuroinflammation as detrimental or beneficial but dependent of a given context which is determined by variable intrinsic and extrinsic components. To what extent is it beneficial?
IV. THE INTERLEUKIN-6 AND CENTRAL NERVOUS SYSTEM REGENERATION
IV.A. GENERALITIES
Tissue injuries lead to the inflammation process. This reaction is the cardinal host defense in response infectious agents. The inflammation process that occurs outside of the brain (systemic inflammation) is characterized by swelling, redness, heat and pain. A the cellular and molecular level this reaction is characterized by a rapid invasion of circulating immune cells (lymphocytes and macrophages) and the induction of inflammatory mediators like the kinins, cyclooxygenase and also cytokines. If these reactions have been well studied outside the CNS they do not have the monopoly on inflammation process as thought by the past (Lucas et al.
2006).
For many years the brain was considered to be devoiced of proper self defense system. Now it is well established the CNS is susceptible to systemic inflammation by leucocytes infiltration and invasion the extravasation process, even if this latter is delayed when compared to the other organs of the body and/or the cross of blood brain barrier (BBB) by inflammatory mediators like the cytokines.
Moreover the CNS is endowed with a capacity to trigger its proper inflammation processes whose characteristics and effectors are almost identical to the systemic inflammation. The key features of CNS inflammation are a glial activation (by astrocytes and microglial cells), oedema, expression of adhesion molecules, invasion of immune cells and the synthesis of inflammatory mediators such as free radicals, prostaglandins.
The neuroinflammation is especially characterized by the rapid production of cytokine molecules that are named “proinflammatory cytokines”. These latter are induced rapidly in response in tissue injury and lead to production of chemoattractant cytokines (chemokines) that recruit immune cells into the CNS and activation of immune cells and endogenous glial cells.
It is well established that microglial cells (the stimulators is unknown but because of the rapidity of the response some authors claim that it is a neuronal abnormal activity that is responsible of microglial activation) and blood-derived macrophages are the first cells that are
proinflammatory cytokines (Streit et al. 1999, Rock et al. 2004). In fact, microglial cells rapidly display an amoeboid morphology (activated microglia) and migrate to the site of the lesion in order to phagocyte the damaged cells and cellular debris (Streit et al. 1999, Bechmann
& Nitsch 2000). Subsequently microglial cells produce various molecules like trophic factors and also cytokines that can exert protective of destructive action of the neighboring cells. This activation of proinflammatory cytokines induces the production of other cytokines by other cells leading to a second “wave” of cellular reactions and cytokine-induced signaling. This phenomenon has clear benefit effect in that it limits proliferation of pathogens but only during a short period of time. It is a sustained excessive inflammation can damage tissue. Because it possess both detrimental and beneficial roles (depending of the context: age, environment) it is of importance to dissect-out the respective role of each of this mediators in view of potential and efficient therapeutics. However it is a difficult task since cytokines that are involved are dependent of the type of injury.
In conclusion, the investigation of their precise and respective role in CNS disease is of a great interest. Among them the interleukin-6 (IL-6) is one of the most important and studied of these proinflammatory agents.