Involvement Of Neuroactive Steroids Research Articles

Axonal transport in a peripheral diabetic neuropathy model: sex-dimorphic features

BackgroundDisruption of axonal transport plays a pivotal role in diabetic neuropathy. A sex-dimorphism exists in the incidence and symptomatology of diabetic neuropathy; however, no studies so far have addressed sex differences in axonal motor proteins expression in early diabetes as well as the possible involvement of neuroactive steroids. Interestingly, recent data point to a role for mitochondria in the sexual dimorphism of neurodegenerative diseases. Mitochondria have a fundamental role in axonal transport by producing the motors’ energy source, ATP. Moreover, neuroactive steroids can also regulate mitochondrial function.MethodsHere, we investigated the impact of short-term diabetes in the peripheral nervous system of male and female rats on key motor proteins important for axonal transport, mitochondrial function, and neuroactive steroids levels.ResultsWe show that short-term diabetes alters mRNA levels and axoplasm protein contents of kinesin family member KIF1A, KIF5B, KIF5A and Myosin Va in male but not in female rats. Similarly, the expression of peroxisome proliferator-activated receptor γ co-activator-1α, a subunit of the respiratory chain complex IV, ATP levels and the key regulators of mitochondrial dynamics were affected in males but not in females. Concomitant analysis of neuroactive steroid levels in sciatic nerve showed an alteration of testosterone, dihydrotestosterone, and allopregnanolone in diabetic males, whereas no changes were observed in female rats.ConclusionsThese findings suggest that sex-specific decrease in neuroactive steroid levels in male diabetic animals may cause an alteration in their mitochondrial function that in turn might impact in axonal transport, contributing to the sex difference observed in diabetic neuropathy.

Involvement of Neuroactive Steroids in Pain, Depression and Anxiety.

Comorbidity between major depressive disorder (MDD), anxiety (generalized anxiety, panic disorder, social anxiety disorder) and pain is a major complicating factor in the diagnosis and treatment of psychiatric and neurological disorders. Although numerous neurotransmitters and/or neuromodulators may be involved, abnormalities in the GABAergic and glutamatergic systems seem to be a common factor in all these disorders. Neuroactive steroids (NASs) have been the object of considerable interest in this area in recent years since they appear to act predominantly on GABA-A and glutamate NMDA receptors. An overview of the possible involvement of NASs in MDD, anxiety and pain is provided in this chapter.

Majonoside-R2 reverses social isolation stress-induced decrease in pentobarbital sleep in mice: Possible involvement of neuroactive steroids

Majonoside-R2 (MR2) is a major ocotillol-type saponin constituent of Vietnamese ginseng. We investigated the effect of MR2 on the social isolation stress-induced decrease in pentobarbital sleep in mice, and elucidated the possible involvement of neurosteroidal sites of the GABA A receptor complex in the pharmacological activity of MR2. MR2 (3.1–6.2 mg/kg, i.p. or 5–10 μg, i.c.v.) dose-dependently reversed the decrease in pentobarbital sleep caused by social isolation stress to the level of sleep in the group-housed mice, but it had no effect on pentobarbital sleep in group-housed mice. Allotetrahydrodeoxycorticosterone (5α-pregnane-3 α,21-diol-20-one, allo-THDOC; 12.5 μg, i.c.v.), the positive allosteric modulator of the GABA A receptor, and α-helical CRF 9-41 (αhCRF; 25 μg, i.c.v.), the corticotropin-releasing factor (CRF) antagonist, also reversed the decrease in pentobarbital sleep caused by social isolation stress. The reversing effects of i.c.v. MR2 and i.c.v. allo-THDOC on the decrease in pentobarbital sleep in isolated mice were significantly attenuated by pregnenolone sulfate (10 μg, i.c.v.), the steroidal negative allosteric modulator of the GABA A receptor. In contrast, when injected i.c.v., MR2, as well as allo-THDOC and αhCRF, significantly reversed the decrease in pentobarbital sleep induced by pregnenolone sulfate (10 μg, i.c.v.) and CRF (10 μg, i.c.v.) in group-housed mice. These results suggest that the reversing effect of MR2 on the social isolation stress-induced decrease in pentobarbital sleep is mediated by the neurosteroid site on the GABA A receptor complex in mice.