d-jnki-1 and Ischemia

JNKs (c-Jun N- terminal kinases) are important transducing enzymes involved in many faces of cellular regulation such as gene expression, cell proliferation and programmed cell death. The activation of JNK pathway is critical for naturally occurring neuronal death during development as well as for pathological death of adult brain following different insults. In particular, JNKs play an important role in excitotoxicity and all related phenomena. Initial research concentrated on defining the components and organization of JNK signalling cascades, but more recent studies have begun to see JNK as the appropriate target for prevent cell loss. We used a specific JNK inhibitor, the cell permeable peptide D-JNKI1, to block JNK action in neuronal death following excitotoxicity in vitro and cerebral ischemia in vivo. Here we review our recent findings and we discuss the possibility of using D-JNKI1 as a therapeutic agent to prevent cell loss in the central nervous system.

Topics: Animals; Central Nervous System; Disease Models, Animal; Enzyme Inhibitors; Hippocampus; Humans; Ischemia; MAP Kinase Kinase 4; Mice; Nerve Degeneration; Neurodegenerative Diseases; Neurons; Peptides; Rats

AM-111, a cell-permeable peptide inhibitor of c-Jun N-terminal kinase, was investigated for its protective effects against ischemic damage of the cochlea in gerbils.. Transient cochlear ischemia was introduced in animals by occluding the bilateral vertebral arteries for l5 minutes. Then, 10 μl of AM-111 at a concentration of l, 10, or 100 μM in hyaluronic acid gel formulation was applied onto the round window 30 minutes after the insult. Gel without active substance was used in a control group. Treatment effects were evaluated by auditory brainstem response (ABR) and histology of the inner ear.. In controls, transient cochlear ischemia caused a 25.0 ± 5.0 dB increase in the ABR threshold at 8 kHz and a decrease of 13.3 ± 2.3% in inner hair cells at the basal turn on Day 7. Ischemic damage was mild at 2 and 4 kHz. When the animals were treated with AM-111 at 100 μM, cochlear damage was significantly reduced: the increase in ABR threshold was 3.3 ± 2.4 dB at 8 kHz, and the inner hair cell loss was 3.1 ± 0.6% at the basal turn on Day 7. The effects of AM-111 were concentration dependent: 100 μM was more effective than 1 or 10 μM.. Direct application of AM-111 in gel formulation on the round window was effective in preventing acute hearing loss because of transient cochlear ischemia.

Topics: Animals; Cochlea; Evoked Potentials, Auditory, Brain Stem; Gerbillinae; Hair Cells, Auditory; Hearing Loss; Ischemia; Peptides