alpha-Melanocyte-stimulating hormone in neurodegenerative processes

Abstract

The fact that inflammatory processes accompany the neuronal cell death in most neurodegenerative disorders, has in recent years inspired to studies on the role of inflammation in the brain and the possibility to prevent or stop the degenerative processes by treatment with anti-inflammatory drugs. Neurodegenerative disorders are often accompanied by a progressive loss of memory, and substances that can improve memory functions are of great interest. We have used two established methods for inducing neurodegeneration in rats (1) global cerebral ischemia, and (2) administration of the excitotoxic amino acid kainic acid (KA), a commonly used model of human temporal lobe epilepsy. An important event in both of these models is excessive glutamate receptor stimulation. The resulting neurodegeneration is accompanied by glial activation and induction of inflammatory factors such as cytokines. Furthermore, hypothermia has been shown to reduce neurodegeneration in both KA-induced excitotoxicity and in cerebral ischemia.

We have investigated the effects of alpha-melanocyte-stimulating hormone (alpha-MSH), on the neurodegenerative process in the animal models mentioned above, as well as its effects on memory and learning in normal and cognitively impaired rats. alpha-MSH is a tridecapeptide derived from proopiomelanocortin (POMC). In the brain, alpha-MSH is mainly produced by neurons in the arcuate nucleus of the hypothalamus and melanocortin receptors have a widespread distribution in the brain. alpha-MSH has been shown to exert anti-inflammatory as well as anti-pyretic effects, and to inhibit the production of pro-inflammatory cytokines and other factors released during inflammation.

The neurodegeneration resulting from global cerebral ischemia was significantly reduced by post-ischemic administration of alpha-MSH. Furthermore, the accompanying astrocyte reaction was ameliorated. The rescuing effect of alpha-MSH following KA-induced excitoxicity was similar to that seen after global cerebral ischemia, and the astrogliosis was reduced. The peripheral administration of alpha-MSH dose-dependently affected the changes in body temperature induced by KA, i.e. both the initial hypothermia and the following longer-lasting hyperthermia. In global cerebral ischemia, the pretreatment with alpha-MSH resulted in a reduction in body temperature during the ischemic period and during the following reperfusion, as well as a potentiation of the reduction in brain temperature. alpha-MSH also resulted in a faster recovery to baseline bodyweight. Furthermore, alpha-MSH was shown to improve long-term memory in naive rats in a dosedependent manner.

These results indicate that alpha-MSH has a rescuing effect on neurons following excessive glutamate receptor stimulation. In addition, alpha-MSH has the potential of improving memory functions both under normal and pathological conditions. These data give support for further studies on alpha-MSH as a means of treatment in neurodegenerative disorders.