Parkinsonian brain

The pathological characteristic of Parkinson s disease is the selective degeneration of dopamine neurons in the pars compacta of the substantia nigra. The mechanism for the loss of neurons remains to be elucidated, and recently apoptosis has been proposed as a death process in Parkinson s disease. For example, the level of a product of the oxidative stress, 4-hydroxy-2-nonenal protein adduct, was found to increase in the nigral neurons of parkinsonian brains. Peroxynitrite (see Figure 13.6) has been proposed to be involved in the neuronal cell death in some neurodegenerative diseases, such as amyotrophic lateral sclerosis. 

B. Halliwell, Oxidative DNA damage in the parkinsonian brain An apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J. Neurochem. 69, 1196-1203 (1997)... 

Mogi M, Togari A, Kondo T, Mizuno Y, Komur e O, Kuno S, Ichinose H, Nagatsu T (2000) Caspase activities and tumor necrosis factor receptor R1 (p55) level ar e elevated in tire substantia nigi a fi om parkinsonian brain. J Neural Transm 107 335—341. 

As in AD, knowdedge of the neurotransmitter deficiency underlying PD, in this case dopamine, has been the basis for the development of therapy. Early studies show ed that cerebral dopamine was concentrated in the shiatum and that levodopa, the precursor to dopamine, could reverse the akinetic effects of the dopamine-depleting agent reserpine in experimental animals (Carlsson et al., 1957, 1958). Eventually, the identification of shiatal dopamine depletion as a key neurochemical finding in parkinsonian brains lead to heatment wdth levodopa in humans and to the subsequent advent of compounds that mimic the effects of dopamine or prolong its action (Table 39.2). 

Yoshimi K, Ren YR, Seki T, Yamada M, Ooizumi H, Onodera M, Saito Y, Murayama S, Okano H, Mizuno Y, Mochizuki H (2005) Possibility for neurogenesis in substantia nigra of parkinsonian brain. Ann Neurol 58 31 0. 

There is considerable body of (indirect) evidence which makes oxidative stress one of the best accepted hypothesis for explaining the cause of Parkinson s disease. For example, the Fe(II)/Fe(III) ratio in the substantia nigra is shifted from 2 1 in the normal brain to 1 2 in Parkinsonian brain.131,132 In the Parkinsonian brain several enzymes which constitute the antioxidative defence mechanisms (glutathione peroxidase, catalase) have a decreased activity, while the activity of superoxide dismutase is increased, relative to the normal brain.133 Furthermore, specific products of radical damage, such as lipid hydroperoxides, were detected at a 10-fold increased level in the Parkinsonian brain.134... 

Sofic, E. Riederer, P. Heinsen, H. Beckmann, H. Reynolds, G.P. Hebenstreit, G. Youdim, M.B. (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J. Neural Transm. 74, 199-205. 

The severity of dementia in PD patients correlates to the severity of Alzheimer s pathology in parkinsonian brains whereby a mild degree of dementia can be ascribed to degeneration of SNC, and a marked degree of cognitive impairment results from additional cortical Alzheimer lesions (Paulus and Jellinger, 1991). The neuropathologi-cal distinction between PD/dementia and PD plus dementia is very difficult. 

Guttman, M. and Seeman, P. (1986) Dopamine D2 receptor density in parkinsonian brain is constant for duration of disease, age and duration of l-DOPA therapy. In M.D. Yahr and K.J. Bergmann (Eds.), Advances in Neurology, Parkinson s Disease, Vol. 45, Raven Press, New York, pp. 

Iron-melanin complex in substantia nigra of parkinsonian brains an X-ray microanalysis. J. Neurochem. 59 1168-1171. 

Nagatsu, T. (1990) Changes of tyrosine hydroxylase in Parkinsonian brains and in the brain of MPTP-treated mice. In M.B. Streifler, A.D. Korczyn, E. Melamed and M.B.H. Youdim (Eds.), Advances in Neurology Parkinson s Disease Anatomy, Pathology and Therapy, Vol. 53, Raven Press, New York, pp. 207-214. 

Riederer, P., Sofic, E., Rausch, W.D., Schmidt, B., Reynolds, G.P., Jellinger, K. and Youdim, M.B.H. (1989c) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J. Neurochem. 52 515-520. 

Rinne, U.K, Ldnnberg, P. and Koskinen, V. (1981) Dopamine receptors in the parkinsonian brain. J. Neural Transm. 51 ... 

Levodopa is the immediate precursor of dopamine and is able to penetrate the brain, where it is converted to dopamine. The site of this decarboxylation in the parkinsonian brain is uncertain, but a.s dopa decarboxylase is not rate limiting, there may be. sufficient enzyme in the remaining dopaminergic nerve terminals. Another possibility is that the conversion occurs in noradrenergic or serotonergic terminals, because the decarboxylase activity in these neurotics is not specific. In any event, the release of dopamine replaced in the brain by Icvodopa therapy must be very abnormal, and it is remarkable that most patients with Parkinson s disease benefit, often dramatically, from its administration. 

Riederer P, Sofic E et al. (1989) Transition metals, ferritin, glutathione, and ascorbic acid in parkinsonian brains. J Neurochem. 52 515-520. 

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