Chemistry Reference
In-Depth Information
supraspinal descending facilitation, and nitroxidative stress [21]. The
O
−•
species is produced from mitochondria and NADPH oxidase, while NOS
enzymes synthesize NO
•
through enhanced nociception and the activation of
the
N
-methyl-D-aspartate receptor. Both
O
−•
and NO
•
form ONOO
−
, which
inactivates the glutamate transporter, manganese superoxide dismutase
(MnSOD), and glutamate synthase, which increases the production of addi-
tional nitroxidative species [10]. In addition to ROS and RNS, other reactive
species also involved in various biological activities include the carbonate
radical (
CO
−•
) and the organic radical, R
•
(thiyl and protein radicals). Metals
such as Cr, Mn, and Fe in their high-valent sates are also involved in reactions
with molecules of biological importance. Reactive intermediates may also be
produced by UV radiation in the presence of oxygen [22].
1.1 DISEASES
1.1.1 Neurodegenerative Diseases
Generally, there are four common features in neurodegenerative diseases,
which are interrelated with one another [23-25]. These include (1) both ROS
and RNS working together to cause damage in the degenerative disease and
also to create a vicious cycle by stimulating proinflammatory gene transcrip-
tion in glia; (2) participation of redox-active (e.g., Cu and Fe) and redox-
inactive (e.g., Zn) metal ions; (3) abnormal functioning of mitochondria; and
(4) accumulation of misfolded or unfolded proteins in brain cells, which
leads to Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's
disease (HD), frontotemporal labor degeneration (FTLD), multiple sclerosis,
and amyotrophic lateral sclerosis (ALS) (Table 1.2) [26]. A recent study
demonstrated the role of RNS in protein misfolding, mitochondrial dysfunc-
tion, and synaptic injury [27]. Most of the folded proteins display toxicity
toward cultured neuronal cells
in vitro
and, hence, may be related to the
degeneration and loss of nerve cells
in vivo
. The molecular mechanism of
toxic effects is not fully understood, but changes in membrane permeability,
influx of Ca
2+
, and oxidative damage induction, followed by apopotosis have
been suggested [26].
The chemistry of neurotoxicity is presented in Figure 1.1 [23]. The
O
−•
species is produced from mitochondrial proteins and mutationally altered or
damaged proteins, which subsequently generate H
2
O
2
. The
•
OH species is
generated through reactions of H
2
O
2
with
O
−•
(Haber-Weiss reaction) and
transition metal ion (generally Cu(I) and Fe(II)) (Fenton reaction). The result-
ing oxidized metal ions (Cu(II) and Fe(III)) can be reduced by cellular reduc-
tants such as thiols, vitamin C, and vitamin E. SOD also transforms
O
−•
to O
2
and H
2
O
2
, while catalase (CAT) removes H
2
O
2
. Oxidation of protein side
chains generate hydroxylated and carbonyl products (Chapters 4 and 5). Oxi-
dation also occurs through halogenated species (e.g., HOCl) (Chapter 3). The
Search WWH ::
Custom Search