We have hypothesized that p75 neurotrophin receptor (p75(NTR))-mediated activation of the pro-apoptotic proteins c-jun, p38 and caspase-3 underlies the neuronal cell loss in dorsal root ganglia (DRG) neurons after axotomy in normal mice, and that this activation is exaggerated in experimental diabetes. To test this hypothesized relationship, we compared the expression of pro-apoptotic proteins in fifth lumbar DRG (L5DRG) neurons of wildtype Balb/c (p75+/+) mice and p75(NTR) knockout (p75-/-) mice, assigned to either non-diabetic control groups or to diabetic (1 month) groups, all with a unilateral sciatic nerve crush produced 10 days before tissue preparation. The absolute number of L5DRG neurons expressing immunoreactivities (IR) for phosphorylated c-jun (P-c-jun-IR), phosphorylated p-38 (P-p38-IR) and cleaved caspase-3 (caspase-3-IR) were estimated in semi-thick sections using the optical fractionator. Nerve crush increased the numbers of P-c-jun-IR and caspase-3-IR neurons in all four groups. On the crush side, diabetes did not exaggerate the increase of P-c-jun-IR or caspase-3-IR neurons in p75+/+ mice, whereas in p75-/- mice diabetes reduced the increase of P-c-jun-IR neurons. Also, in p75-/- mice there was fewer caspase-3-IR cells on the intact and crushed side in comparison with p75+/+ mice independent of the presence of diabetes. This study demonstrates that (1) diabetes of 1 month's duration does not potentiate the expression of three pro-apoptotic markers p38, caspase-3 and P-c-jun neither in intact neurons nor after nerve crush, and that (2) p75(NTR) is required for activation of the pro-apoptosis signal caspase-3 after nerve crush in both diabetic and non-diabetic mice.