Bg. Jenkins et al., NONINVASIVE NEUROCHEMICAL ANALYSIS OF FOCUS EXCITOTOXIC LESIONS IN MODELS OF NEURODEGENERATIVE ILLNESS USING SPECTROSCOPIC IMAGING, Journal of cerebral blood flow and metabolism, 16(3), 1996, pp. 450-461
Water-suppressed chemical shift magnetic resonance imaging was used to
detect neurochemical alterations in vivo in neurotoxin-induced rat mo
dels of Huntington's and Parkinson's disease. The toxins were: N-methy
l-4-phenylpyridinium (MPP(+)), aminooxyacetic acid (AOAA), 3-nitroprop
ionic acid (3-NP), malonate, and azide. Local or systemic injection of
these compounds caused secondary excitotoxic lesions by selective inh
ibition of mitochondrial respiration that gave rise to elevated lactat
e concentrations in the striatum. In addition decreased N-acetylaspart
ate (NAA) concentrations were noted at the lesion Site Over time. Meas
urements of lactate washout kinetics demonstrated that t(1/2) followed
the order: 3-NP approximate to MPP(+) AOAA approximate to malonate wh
ich parallels the expected lifetimes of the neurotoxins based On their
mechanisms of action. Further increases in lactate were also Caused b
y intravenous infusion of glucose. at least part of the excitotoxicity
is mediated through indirect glutamate pathways because lactate produ
ction and lesion size were diminished using unilateral decortectomies
(blockade of glutamatergic input) or glutamate antagonists (MK-801). L
esion size and lactate were also diminished by energy repletion with u
biquinone and nicotinamide. Lactate measurements determined by magneti
c resonance agreed with biochemical measurements made using freeze cla
mp techniques. Lesion size as measured with MR, although larger by 30%
, agreed well with lesion size determined histologically. These experi
ments provide evidence for impairment of intracellular energy metaboli
sm leading to indirect excitotoxicity for all the compounds mentioned
before and demonstrate the feasibility of small-volume metabolite imag
ing for in vivo neurochemical analysis.