X-irradiation-induced changes in the diffusion parameters of the developing
rat brain.
Sykova E, Svoboda J, Simonova Z, Lehmenkuhler A, Lassmann H
Laboratory of Cellular Neurophysiology, Institute of Experimental Medicine,
Prague, Czech Republic.
Three diffusion parameters of brain tissue, extracellular space volume
fraction (alpha), tortuosity (lambda) and non-specific uptake (kappa')
of tetramethylammonium were studied in the somatosensory neocortex and
subcortical white matter of the rat during postnatal development (postnatal
days 2-21) after X-irradiation at postnatal days 0-1. The diffusion parameters
were determined from extracellular concentration-time profiles of tetramethylammonium.
The tetramethylammonium concentration was measured in vivo with ion-selective
microelectrodes positioned 130-200 microns from an iontophoretic source.
X-irradiation with a single dose of 40 Gy resulted in typical early morphological
changes in the tissue, namely cell death, DNA fragmentation, extensive
neuronal loss, blood-brain barrier damage, activated macrophages, astrogliosis,
increase in extracellular fibronectin and concomitant changes in all three
diffusion parameters. The changes were observed as early as 48 h post-irradiation
(at postnatal days 2-3) and still persisted at postnatal day 21. On the
other hand, X-irradiation with a single dose of 20 Gy resulted in relatively
light neuronal damage and loss, while blood-brain barrier damage, astrogliosis
and changes in diffusion parameters were not significantly different from
those found with 40 Gy. It is known that the volume fraction of the extracellular
space in the non-irradiated cortex is large in newborn rats and diminishes
with age [Lehmenkuhler A. et al. (1993) Neuroscience 55, 339-351]. X-irradiation
with a single dose of 40 or 20 Gy blocked the normal pattern of volume
fraction decrease during postnatal development, and in fact brought about
a significant increase. At postnatal days 4-5, alpha increased to 0.49
+/- 0.036 in layer III, 0.51 +/- 0.042 in layer IV, 0.48 +/- 0.02 in layer
V, 0.48 +/- 0.028 in layer VI and 0.48 +/- 0.025 in the white matter. The
large increase in alpha persisted three weeks after X-irradiation. Tortuosity
and non-specific uptake decreased significantly at postnatal days 2-5;
at days 8-9 they were not significantly different from those of control
animals, while they increased significantly at days 10-21. Less pronounced
but significant changes in all three diffusion parameters were also found
in areas in the ipsilateral hemisphere adjacent to directly X-irradiated
cortex. Compared to the control animals [Lehmenkuhler A. et al. (1993)
Neuroscience 55, 339-351], a significant decrease of alpha, lambda and
kappa' was found in the contralateral hemisphere 48-72 h after X-irradiation.
Later, alpha values were not significantly different from those in control
animals. The decrease in lambda persisted at postnatal days 4-5. A significant
increase in lambda and kappa' was found at postnatal days 18-21. We conclude
that X-irradiation of the brain in the early postnatal period, even when
it results in only relatively light damage, still produces changes in all
three diffusion parameters, particularly a large increase in extracellular
space volume fraction in all cortical layers, and in the subcortical white
matter. Such changes in extracellular volume fraction of the brain can
contribute to impairment of signal transmission, e.g. by diluting ions
and neuroactive substances released from cells, and can play an important
role in functional deficits, as well as in the impairment of developmental
processes. Moreover, the increase in tortuosity (inferred from the decrease
in apparent diffusion coefficient) in the X-irradiated cortex, as well
as in the contralateral hemisphere, suggests that, even when extracellular
volume is large, the diffusion of the substances is substantially hindered.