No quiet surrender: molecular guardians in multiple sclerosis brain

The brain under immunological attack does not surrender quietly. Investigation of brain lesions in multiple sclerosis (MS) reveals a coordinated molecular response involving various proteins and small molecules ranging from heat shock proteins to small lipids, neurotransmitters, and even gases, which provide protection and foster repair. Reduction of inflammation serves as a necessary prerequisite for effective recovery and regeneration. Remarkably, many lesion-resident molecules activate pathways leading to both suppression of inflammation and promotion of repair mechanisms. These guardian molecules and their corresponding physiologic pathways could potentially be exploited to silence inflammation and repair the injured and degenerating brain and spinal cord in both relapsing-remitting and progressive forms of MS and may be beneficial in other neurologic and psychiatric conditions.It is difficult to say a favorable word about a terrible disease, but one of the positive features of multiple sclerosis (MS) is the remarkable capacity for patients to spontaneously recover from neurologic deficits that are attributed to inflammatory attacks on the CNS. About 80% of patients initially present with a decade or more of relapsing attacks in various areas of the CNS. Most of the neurologic deficits in these recurrent acute attacks, known as relapses after the initial episode, resolve nearly completely over a few days to a few weeks (1). For example, an attack on the optic nerve can leave an individual unable to read for a few days or weeks, but in many cases, there is full recovery of visual acuity after the initial neurologic insult. An attack within the pyramidal system in the brain or spinal cord may cause paralysis of a limb, but often there is recovery from this deficit over days and weeks in the early stages of MS. Despite these remissions, the course of disease advances over a decade or more in about a quarter of individuals. In these unfortunate individuals, relapsing-remitting disease transitions to secondary progressive MS, which is characterized by a large burden of disability and a lack of distinct relapses (1).The substantial and remarkable recovery (remission) from an inflammatory insult (relapse) is a well-known phenomenon; however, more attention has been given to analyzing the inflammation that produces clinical deficits than to the processes that account for remission. The brain in MS frequently responds to immune damage with an array of molecules that serve to protect it from further damage and to foster recovery. This beneficial response to injury may be coordinated. Both cells extrinsic and intrinsic to the CNS are involved in the production of these guardian molecules. Some guardian molecules enter the somewhat privileged site of the brain via infiltrating immune cells (1–6), still others are present at the blood-brain barrier that forms an interface between the immune system and the brain (7–11), while others are produced within the CNS itself (12–35).This Review will describe these guardian molecules including protective cytokines like type 1 interferon, IL-10, and IL-27; the neurotrophins; neurotransmitters like GABA; antioxidants; small lipids present in the normal myelin sheath; nuclear hormone receptors; amyloid-forming molecules; and serpins and other inhibitory proteins. All these molecules may serve as platforms for novel restorative therapies, provided they can be delivered to the brain structures under attack.