CaveMan wrote:As you may suspect my feelings are all these and many more factors combine to weaken the body and open the door to chronic disease, and correction of as many as possible is the most probable path to healing.
Leonard wrote:Is this a pathway where our metabolism is going wrong (I talk here only about the second progressive phase)? I would be interested in your views..
Serum carnitine and disabling fatigue in multiple sclerosis.
Fukazawa T, Sasaki H, Kikuchi S, Hamada T, Tashiro K.
Hokuyukai Neurology Hospital, Sapporo, Japan.
The serum concentrations of total, free and acylcarnitine were compared in 25 patients with multiple sclerosis (MS) and among age- and sex-matched normal controls by the new enzymatic cycling method in order to clarify whether the fatigue in MS might be due to possible carnitine-related fatty acid metabolic abnormalities in the mitochondria of skeletal muscles. Patients with MS were divided into those with and those without excessive fatigue. Levels of total and free carnitine were not significantly different between MS patients and normal controls. Levels of acylcarnitine, whose decrease in chronic fatigue syndrome has been reported, were also similar between MS patients and normal controls. There was no difference in these carnitine levels between MS patients with and without excessive fatigue. We argue that acylcarnitine deficiency and fatty acid metabolic dysfunction in mitochondria are not relevant to the excessive fatigue in patients with MS, and further explanatory investigations are to be sought.
Energy deficiency and dysfunction of Na,K-ATPase are common consequences of many pathological insults and stress. Glutamate through cyclic guanosine monophosphate (GMP) and cyclic GMP-dependent protein kinase (PKG) has been shown to stimulate α2/3-Na,K-ATPase activity in the CNS (58). Thus, a slight impairment of this pathway may amplify the disruption of ion homeostasis in the presence of a non-lethal insult. Studies in rats suggest that basal age-related decline in sodium pump activity is a consequence of changes in different steps of the cyclic GMP-PKG pathway. On the other hand, age-related reduction in glutamate-positive modulation of cerebellar α2/3-Na,K-ATPase is linked to a defective PKG signaling pathway (59). The loss of the ability of α2/3-Na,K-ATPase to respond to glutamate through a cyclic GMP-PKG cascade could be a failure in an important mechanism for rectifying ionic disturbances that may be present in aging processes and may predispose to or potentiate an effect of stress in the manifestation of age-related degenerative disorders. In fact, chronic predictable and unpredictable stress decrease the neuronal Na,K-ATPase activity and high levels of glucocorticoid have been detected in 24-month-old rats (Munhoz CD, Scavone C, unpublished results), which could induce a further reduction of ATP levels during a neurological insult. It is interesting to note that the aging process (30-month-old animals) induces up-regulation in constitutive NFκB binding activity in the frontal cortex, which in the presence of glucocorticoid levels could potentiate LPS-induced NFκB activation and an increase in mRNA of proinflammatory genes (9). In addition, rats with increased HPA reactivity induced by prenatal stress or by the absence of neonatal handling show an early decline of cognitive functions associated with the hippocampus, as well as increased propensity to self-administer drugs such as amphetamine and cocaine (55). In addition, exposure to both chronic restraint and unpredictable stress increased cocaine-induced locomotion and basal corticosterone plasma levels and chronic unpredictable stress also displayed the largest locomotor response following a challenge dose with cocaine compared with control and chronic restraint stress groups (60). Drug abuse is associated with changes in brain function and neurodegenerative processes, which, for some drugs, have been shown to be associated with the induction of apoptotic/necrotic cell death (Lepsch LB, Munhoz CD, Kawamoto EM, Lima LS, Scavone C, unpublished results). Thus, life-long patterns of HPA function are probably important to determine the susceptibility of the body to stress or insults during the aging process.
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