Stz20 Stz50

stz 100 CAl667G0X0tA

Figure 1 NBF and nerve vascular resistance of control (Con; n = 8), streptozotocin-diabetic neuropathy (STZ; n = 5), and animals given lipoic acid supplements at doses of 20 mg/kg (STZ20; n = 6), 50 mg/kg (Con50; STZ50; n = 5), and 100 mg/kg (STZ100; n 8). Lipoic acid supplementation results in normal flow and nerve vascular resistance. Significance of difference, STZ-supplemented vs. STZ. Bars, SE. (From Ref. 12.)

Figure 2 Sciatic nerve GSH concentrations in controls (Con) and on restricted caloric intake (Con[R]), streptozotocin diabetic (STZ), a-tocopherol-depleted (-), and supplemented with lipoic acid at 20, 50, and 100 mg/kg. Lipoic acid supplementation resulted in a dose-dependent prevention of GSH depletion. Significance of difference, vs. control, * p < 0.05; *** p < 0.001; vs. STZ: a, p < 0.05: t, p < 0.001. (From Low et al., Diabetes 1997; 46 (suppl 2): S38-S42.

Figure 2 Sciatic nerve GSH concentrations in controls (Con) and on restricted caloric intake (Con[R]), streptozotocin diabetic (STZ), a-tocopherol-depleted (-), and supplemented with lipoic acid at 20, 50, and 100 mg/kg. Lipoic acid supplementation resulted in a dose-dependent prevention of GSH depletion. Significance of difference, vs. control, * p < 0.05; *** p < 0.001; vs. STZ: a, p < 0.05: t, p < 0.001. (From Low et al., Diabetes 1997; 46 (suppl 2): S38-S42.

physiology, and indices of oxidative stress in peripheral nerve at 1 month after onset of diabetes and in age-matched control rats (12). Lipoic acid, in doses of 20, 50, and 100 mg/kg, was administered intraperitoneally five times per week after onset of diabetes. NBF in EDN was reduced by 50%; lipoic acid did not affect NBF of normal nerves but improved that of EDN in a dose-dependent fashion. After 1 month of treatment, lipoic acid-supplemented rats (100 mg/kg) had normal NBF (Fig. 1). The most sensitive and reliable indicator of oxidative stress was a reduction in GSH, which was significantly reduced in EDN; it was improved in a dose-dependent manner in lipoic acid-supplemented rats (Fig. 2). The conduction velocity of digital nerve was reduced in EDN and was significantly improved by lipoic acid.

IV. ANTIOXIDANT THERAPY WITH a-LIPOIC ACID IN ISCHEMIA-REPERFUSION INJURY

Reperfusion after peripheral nerve ischemia results in reduced reperfusion and a breakdown of the blood-nerve barrier (13). After 1 h of ischemia, the permeability-surface area product (PA) is unaltered but becomes significantly greater with reperfusion. After 3 h of ischemia, PA is increased and becomes further increased with reperfusion (13). Reperfusion results in a significant increase in endoneurial lipid hydroperoxides (14). Because a-lipoic acid is a powerful lipophilic antioxidant, we evaluated its efficacy in protecting peripheral nerve from reperfusion injury, using our established model of ischemia-reperfusion injury. We used male Sprague-Dawley rats, 300 ± 5 g. Surgical ligation of the supplying arteries to the sciatic-tibial nerve of the right hindlimb was performed for predetermined periods of ischemia (either 3 or 5 h), followed by the release of the ligatures. Lipoic acid (100 mg/kg/day) was given by intraperitoneal injection daily for 3 days pre- and postsurgery. The same dose of saline was given intraperitoneally to the control rats. A behavioral score of clinical neurological deficits and electrophysiology of motor and sensory nerves was analyzed at 1 week after the surgery. After the electrophysiological examination, the sciatic-tibial nerve was fixed in situ and embedded in epon. One-micron sections with toluidine blue staining were evaluated for ischemic fiber degeneration (IFD) and edema, using previously described methodology (15).

Distal sensory conduction (amplitude of sensory action potential and sensory conduction velocity of digital nerve) was significantly improved in 3-h ischemia treated with lipoic acid (p < 0.05). Lipoic acid also improved IFD and edema. The changes after a longer duration of ischemia (5 h) were fewer. These results suggest that the therapeutic window of a-lipoic acid might be relatively narrow but still has some protective effect on peripheral nerve against mild ischemia and reperfusion insults, especially on distal sensory nerves.

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