Table 1.
Preclinical and clinical evidences for dysregulation in neurosteroidogenesis in neuropsychiatric and neurologic disorders.
| Disease | Experimental studies | |
|---|---|---|
|
| ||
| Mouse / Rat | Human | |
| Neuropsychiatric disorders | ||
| Anxiety disorders | Anxiolytic-like effects of 3α, 5α-THP in several animal models (12, 68). Anxiolytic-like effects of TSPO ligands in animal models (117). |
Increased serum levels of 3α, 5α-THP and 3α, 5β-THP, and decreased 3β, 5α-THP levels in patients with panic disorder (68). No change in 3α, 5α-THP levels in patients with generalized anxiety disorders (68). Decreased TSPO expression in platelets and lymphocytes (104). Anti-panic effects of TSPO ligands in experimental induced anxiety (117). |
| Depression | Antidepressant-like effects of 3α, 5α-THP (13). Decreased brain 3α, 5α-THP levels in animal models of depression, and normalization by antidepressant treatment (75-77). |
Decreased cerebrospinal fluid and serum 3α, 5α-THP levels, and normalization by antidepressant drugs (214, 215). Decreased serum levels of pregnenolone, progesterone, 3α, 5α-THP, 3α, 5β-THP, DHEA, 3α, 5α-androsterone and 3α, 5β-androsterone in women with a history of depression (69). |
| Premenstrual dysphoric disorder (PMDD) | Progesterone withdrawal model of PMDD associated with a upregulation of extrasynaptic α4/δ GABAA receptors and decreased sensitivity to benzodiazepines (58). | Symptoms start at ovulation, paralleling the rise in progesterone and 3α, 5α-THP levels, and severity reaches its maximum at the neuroactive steroid peak (70). Administration of progesterone or 3α, 5α-THP exacerbates negative mood symptoms in PMDD patients (70). |
| Post-traumatic stress disorder (PTSD) | Decreased brain 3α, 5α-THP in the socially isolated mouse model of PTSD (78). Ganaxolone improves behavioral deficits in the socially isolated mouse model of PTSD (216). |
Decreased cerebrospinal fluid 3α, 5α-THP concentrations (217). Decreased TSPO expression in platelets (104). |
| Bipolar disorder | -- | Increased pregnenolone and DHEA levels in posterior cingulate and parietal cortex (72). Increased plasma progesterone and 3α, 5α-THP levels (218). Decreased TSPO expression in platelets (104). |
| Schizophrenia | Increased cerebral cortical 3α, 5α-THP following olanzapine and clozapine administration in rats (80). | Increased pregnenolone and DHEA levels in posterior cingulate and parietal cortex (72). Decreased 3α, 5α-THP levels in parietal cortex (72). Decreased TSPO expression in platelets (104). Pregnenolone treatment improves cognition and negative symptoms in patients with schizophrenia (81). |
| Addiction | 3α, 5α-THP has rewarding properties (20, 21, 219). Neuroactive steroids have ethanol-like discriminative stimulus properties (22, 102, 191). Acute administration of psychoactive drugs with abuse liability increases neuroactive steroid levels (25-30). Neuroactive steroids modulate ethanol and cocaine intake (22, 204, 205, 220-222). Overexpression of P450scc in the ventral tegmental area increases 3α, 5α-THP and reduces ethanol reinforcement and consumption (161). |
Increased plasma 3α, 5α-THP levels in adolescents following alcohol intoxication (195, 196). Decreases serum 3α, 5α-THP and 3α, 5α-THDOC during alcohol withdrawal (73). Neuroactive steroids mediate subjective effects of ethanol (198, 200). |
| Neurological disorders | ||
| Epilepsy | Anticonvulsant effects of 3α, 5α-THP in several animal models (14, 84). | Clinical trials with ganaxolone (82) and progesterone (83). 3α, 5α-THP treatment for pediatric super-refractory status epilepticus (223). |
| Alzheimer's disease | Decreased neuroactive steroid precursors in brain of 3×TgAD mice (88). Neuroprotective and neurotrophic effects of 3α, 5α-THP in 3×TgAD mice (42, 94). Up-regulation of glial TSPO (104). TSPO ligands reverse AD-related neuropathology in 3×TgAD mice (116). Progesterone administration increases progesterone and 3α, 5α-THP levels in the cortex of APPswe+PSEN1Δe9 mice; it also improves cortically-mediated but not hippocampal-mediated cognitive tasks (156, 157). Increased 17β-HSD10 expression in brains of Alzheimer's disease mouse models (179). |
Decreased prefrontal cortex 3α, 5α-THP levels, which are inversely correlated with neuropathological disease stage (89). Decreased plasma 3α, 5α-THP levels in people in the early stages of AD (154). Elevated glial TSPO expression appears early in disease and co-localizes with neuropathology (121). Increased expression of 17β-HSD10 in activated astrocytes (164). |
| Parkinson's disease | 3α, 5α-THP restores tyrosine hydroxylase neurons and improves motor performance in MTPT-treated mice (43). | Decreased dihydroprogesterone and 3α, 5α-THP levels in plasma and liquor (90). |
| Multiple sclerosis | Decreased expression of 3α-HSD and 3α, 5α-THP levels in brain of mice with experimental autoimmune encephalomyelitis (39). 3α, 5α-THP treatment attenuates experimental autoimmune encephalomyelitis neuropathology in mice (39). Neuroactive steroid levels in rats are altered in a brain region and sex dependent manner (85). |
Decreased 5α-reductase expression and 3α, 5α-THP levels in the white matter (39). Increased TSPO expression in white matter lesions correlates with brain damage (104). Increased levels of neuroactive steroid precursors and decreased levels of dihydroprogesterone, 3α, 5α-THP, and dihydrotestosterone in plasma and cerebrospinal fluid of male patients (86). |
| Niemann-Pick type C disease | Decreased steroidogenic enzymes expression, as well as pregnenolone and 3α, 5α-THP brain levels in NP-C mice (44). Neuroprotective effect of 3α, 5α-THP in NP-C mice (44). |
-- |
| Diabetic neuropathy | Decreased brain and peripheral neuroactive steroid levels in rats with streptozotocin-induced diabetes (92). Neuroprotective effects of progesterone, dihydroprogesterone and 3α, 5α-THP in streptozotocin-induced diabetic neuropathy in rats (96). |
-- |
| Traumatic brain injury | Neuroprotective effects of progesterone and 3α, 5α-THP in rats (31). Progesterone and DHEA levels correlate with neurological recovery from TBI in mice (91). |
Negative outcome of clinical trials with progesterone (224). |
| Stroke | Neuroprotective effects of progesterone and 3α, 5α-THP in mice (97). | Increased TSPO expression in primary lesion and remote areas (104). |