Charcot­Marie­Tooth type 1A drug therapies: role of adenylyl cyclase activity and G­protein coupled receptors in disease pathomechanism.

Charcot­Marie­Tooth type 1A (CMT1A) is a dysmyelinating disease of the peripheral nervous system that results in a slow progressive weakening and wasting of the distal muscles of the upper and lower limbs. Despite extensive research and clinical trials there is still no treatment for CMT1A that results in complete neurological improvement. Recent studies investigating various pharmacological modulators of adenylyl cyclase activity, including ascorbic acid and ligands of G protein­coupled receptors (GPCRs), provide hope for future treatments of this type of hereditary motor and sensory neuropathy. A review of mechanisms of action of several compounds tested for CMT1A in pre­clinical and clinical studies ascorbic acid, onapristone, PXT3003 (baclofen, naltrexone, and sorbitol), and ADX71441, very clearly indicates an important role for adenylyl cyclase activity and GPCRs in the pathomechanism of the disease. Metabotropic γ­aminobutyric acid receptors (GABABR), subtype mu (µ) opioid receptors (MOR), and muscarinic acetylcholine receptors (mACh) appear to be particularly significant in both pathogenesis and treatment, and their activation may exert a similar and synergistic effect on the physiology of Schwann cells as well as neurons. These receptors participate in proliferation and differentiation of Schwann cells and influence excitatory transmission in neurons. We also hypothesize that onapristone might act through a non­classical mechanism via membrane progesterone receptor (mPR) and cAMP signaling. This review endeavors to outline a pathway leading inversely from therapy to an indispensable role for adenylyl cyclase activity and GPCRs in the modulation of dosage sensitive peripheral myelin protein (PMP22) gene expression.

Volumetric response of the adult brain to seizures depends on the developmental stage when systemic inflammation was induced.

Inflammation has detrimental influences on the developing brain including triggering the epileptogenesis. On the other hand, seizure episodes may induce inflammatory processes and further increase of brain excitability. The present study focuses on the problem whether transitory systemic inflammation during developmental period may have critical importance to functional and/or structural features of the adult brain. An inflammatory status was induced with lipopolysaccharide (LPS) in 6- or 30-day-old rats. Two-month-old rats which experienced the inflammation and untreated controls received injections of pilocarpine, and the intensity of their seizure behavior was rated during a 6-hour period. Three days thereafter, the animals were perfused; their brains were postfixed and subjected to magnetic resonance imaging (MRI) scans. Then, volumes of the brain and of its main regions were assessed. LPS injections alone performed at different developmental stages led to different changes in the volume of adult brain and also to different susceptibility to seizures induced in adulthood. Moreover, the LPS pretreatments modified different volumetric responses of the brain and of its regions to seizures. The responses showed strong inverse correlations with the intensity of seizures but exclusively in rats treated with LPS on postnatal day 30. It could be concluded that generalized inflammation elicited at developmental stages may have strong age-dependent effects on the adult brain regarding not only its susceptibility to action of a seizuregenic agent but also its volumetric reactivity to seizures.

[Therapeutic perspective in hereditary polyneuropathies]. / Perspektywy terapii w polineuropatiach genetycznie uwarunkowanych.

Hereditary motor and sensory neuropathies (HMSN) also called as Charcot-Marie-Tooth disorders (CMT) are extremely heterogeneous group of disorders of peripheral nervous system. Over 80 genes have been reported in different types of CMT. In all CMT affected patients the main symptoms are slowly progressive wasting of the distal muscles of the lower and upper limbs. To date no efficient therapeutic approach basing upon molecular pathology of CMT has been proposed. This review presents the current state of knowledge concerning clinical, molecular pathogenesis and experimental therapy aspects in CMT disorders. Additionally the possibilities resulting from the use of the yeast model to the identification of new therapeutic substances as well as of neurotoxins are also discussed.