Dietary carnitine supplements slow disease progression in a putative mouse model for hereditary ceroid-lipofuscinosis

Abstract

The childhood ceroid-lipofuscinoses are a group of autosomal recessively inherited disorders characterized by massive accumulation of autofluorescent lysosomal storage bodies in neurons as well as other cell types. The storage body accumulation is accompanied by severe degeneration of the central nervous system that results in blindness, cognitive and psychomotor degeneration, and premature death. On the basis of pathologic and biochemical criteria, a hereditary disease in the mnd mouse strain has been proposed as a model for certain types of human ceroid-lipofuscinosis. Experimental evidence suggests that the storage body accumulation in humans with juvenile and late-infantile ceroid-lipofuscinosis is linked to altered carnitine biosynthesis. On the basis of the latter observation, a study was performed to determine whether dietary carnitine supplements could slow the disease progression in the mnd mouse model. Carnitine supplementation begun at 4 weeks of age did not slow the retinal degeneration that is characteristic of this disease. It did, however, significantly elevate brain carnitine levels, slow the accumulation of autofluorescent storage bodies in brain neurons, and prolong the lifespans of the treated animals. These findings suggest that there is a link between carnitine biosynthesis and the disease pathology and indicate that carnitine supplementation may be beneficial in slowing the disease progression in humans with certain types of hereditary ceroid-lipofuscinosis.

Mitochondrial oxidative metabolism in motor neuron degeneration (mnd) mouse central nervous system

“…Trimethyllisine residue, a precursor of carnitine biosynthesis, is present in the autofluorescence storage bodies of brain neurons of mnd mice. Consistent with this assumption, high dietary L‐CAR supplementation slows the accumulation of autofluorescence storage bodies in brain neurons of mnd mice and prolongs their lifespan (but has no effect on retinal degeneration) (Katz et al. , 1997).…”

“…This partial recovery may depend on the dose of drug administered in the experiments. A low dose of L‐CAR was used, about 50–80 times lower than that previously reported to decrease lipofuscin accumulation in mnd mice (Katz et al. , 1997).…”

Animal model of dementia induced by entorhinal synaptic damage and partial restoration of cognitive deficits by BDNF and carnitine

“…BDNF seems to be applicable to the treatment of degenerative disease, and carnitine can be used to enhance neuronal plasticity and thereby delay the onset of degenerative diseases. Because carnitine and its derivatives have been tested for anti‐aging effects in many studies (Sershen et al, 1991; Bertoni‐Freddari et al, 1994; Taglialatela et al, 1994; Caprioli et al, 1995; Katz et al, 1997; Aureli et al, 2000; Ando et al, 2001; Kaur et al, 2001; Lohninger et al, 2001; Liu et al, 2002), it is expected that carnitine will have an expanding role in preventive medicine.…”

A mouse gene knockout model for juvenile ceroid‐lipofuscinosis (batten disease)

“…The knockout mice should also be useful in evaluating potential therapies that could slow or halt the progression of Batten disease symptoms. On the basis of several studies, dietary supplementation with antioxidants, polyunsaturated fatty acids, or with carnitine have been proposed as treatments, with the potential of slowing the advancement of the disease pathology (Bennett et al, 1994;Katz et al, 1997b;Santavuori and Westermarck, 1984;Siakotos et al, 1974). Evaluating these or other potential treatments using human subjects in con- trolled trials would be quite difficult given that the disease is relatively rare.…”