Failure of the Neurotrophic ACTH(4–10) Analogue (BIM 22015) to Attenuate the AF64A-Induced Cholinergic Lesion in Rat Hippocampus

Abstract

ACTH derived peptides including ACTH(4–9) and ACTH (4–10) possess a neurotrophic potential (Gispen, 1990), but are devoid of corticotrophic action (De Wied, 1969). These ACTH-analogues have been shown to facilitate various forms of neuronal plasticity and to accelerate nerve recovery from mechanical trauma or neurotoxic damage. In the periphery, the neurotrophic properties of ACTH-like peptides have been most extensively studied in the rat or rabbit nerve crush model (Strand and Kung, 1980; Bijlsma et al., 1983; Tonnaer et al., 1992). Beneficial effects have also been achieved in neuropathies of various etiologies in rat and man, including cisplatin- or toxol-induced neuropathy (Gerritsen von der Hoop et al., 1990; Hamers et al., 1993) or diabetic neuropathy (Van der Zee et al., 1990). In the central nervous system, however, the efficacy of these peptides is less convincing and appears to depend on the type of damage and the brain region studied. Although in the rat ACTH fragments reduce hippocampal morphologic correlates of brain aging (Landfield et al., 1981) and improve behavioural recovery from septal lesions and parafascicular thalamic nucleus injury (Isaacson and Poplawsky, 1983; Nyakas et al., 1985), neither serotonergic fibers degenerating in the aging rat hippocampus nor neocortical or hippocampal lesions were affected by ACTH (4–9) (Van Luijtelaar et al., 1992; Mc Daniel et al., 1991). Moreover, no positive effects on cognitive functioning or neurotransmitter markers in patients with dementia of the Alzheimer’s type have been found (Jolkkonen et al., 1985; Miller et al., 1993). In the present investigation we addressed the question whether the ACTH (4–10) analogue has the potential to attenuate a cholinergic lesion of the septo-hippocampal pathway induced by the cholinergic neurotoxin ethylcholine aziridinium (AF64A). For this purpose, AF64A-treated rats received once or twice daily injections of various doses of ACTH(4–10) for 3 weeks. ACTH(4–10)-treatment was started either 1 week before or 1 week after AF64A-injection. The efficacy of ACTH(4–10) was determined by measuring changes in cholinergic and serotonergic markers in the hippocampus.