org-2766 and Nerve-Degeneration

ACTH-like neuropeptides have been investigated in various paradigms such as cognition, neuronal damage and neuronal excitation. All their effects may be collectively described as modulation of neural plasticity. However, the mechanism of action accounting for these effects remains to be demonstrated. This report is an overview of the data and has incorporated some additional findings of the influence of the ACTH4-9 analog, Org2766, on neuronal excitation, especially in the hippocampus. An interaction with NMDA receptors may account for the various aspects of plasticity. Based on recent findings demonstrating that the ACTH4-9 analog counteracts both the NMDA antagonist, AP5, and NMDA-induced explosive running behavior, the hypothesis is put forward that glutamatergic neurotransmission is involved in behavioral changes induced by the ACTH4-9 analog.

Topics: Adrenocorticotropic Hormone; Aging; Animals; Anticonvulsants; Arousal; Brain; Hippocampus; Limbic System; Mental Recall; Models, Neurological; Nerve Degeneration; Neuronal Plasticity; Neuropeptides; Peptide Fragments; Rats; Synaptic Transmission

Ototoxicity and neurotoxicity are among the most serious side-effects of cisplatin therapy. Previous experiments have shown that neurotoxicity can be delayed or prevented by treatment with the melanocortin-derived peptide ORG 2766, and ACTH4-9 analog. A remedy against ototoxicity is not available. In this study we describe cisplatin-induced abnormalities in cochlear potentials in guinea pigs. These included changes in compound action potential (CAP), cochlear microphonics (CM) and summating potential (SP) at frequencies from 500 Hz to 16 kHz. Cisplatin (2 mg/kg for 8 days) reduced CAP amplitude with the effect becoming more pronounced at higher frequencies. Cisplatin also reduced CM and SP. Concurrent treatment with ORG 2766 prevented cisplatin ototoxicity partially or completely in four out of ten animals. In the other six animals the effects were comparable to those seen in control animals not treated with the peptide. The protective effects found with this neurotrophic peptide warrant further experimentation.

Topics: Acoustic Stimulation; Action Potentials; Adrenocorticotropic Hormone; Animals; Audiometry, Evoked Response; Cisplatin; Cochlea; Cochlear Microphonic Potentials; Female; Guinea Pigs; Nerve Degeneration; Peptide Fragments; Placebos; Vestibulocochlear Nerve

Forty adult rats of both genders were randomly assigned to one of four factorial groups and prepared with either medial frontal or sham lesions. On the day of surgery osmotic mini-pumps that had been prepared to deliver either 12.5 micrograms of ACTH(4-9) analog per 24 h or saline for the next 14 days were installed in a subcutaneous location. One month following surgery, these animals were studied in an avoidance conditioning experiment. Four to 6 months later their abilities to learn a water maze win-shift spatial strategy was investigated. The brain-damaged rats were found to be deficient on all behavioral measures examined: errors to criterion, days to criterion, and perseverative errors. Although post-neurosurgical administration of the ACTH 4-9 analog has been shown to improve behavioral recovery from brain damage in some studies, the peptide failed to improve the behaviors examined here.

Topics: Adrenocorticotropic Hormone; Animals; Cerebral Cortex; Cognition; Female; Learning; Male; Nerve Degeneration; Peptide Fragments; Rats; Space Perception; Thalamic Nuclei; Thalamus