DIMORFISMO SESSUALE DELLE PATOLOGIA DEL SISTEMA NERVOSO: POSSIBILI TARGETS TERAPEUTICI

Transcription

1 DIMORFISMO SESSUALE DELLE PATOLOGIA DEL SISTEMA NERVOSO: POSSIBILI TARGETS TERAPEUTICI

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3 GENDER DIFFERENCES IN ALZHEIMER S DISEASE Epidemiological studies support a higher prevalence and incidence in women (Moreira et al., 2008) At variance, to what observed in young male and old females, mitochondria of young females are protected against the increased in peroxide production caused by β-amyloid (Lloret et al., 2008) Higher plaque load is observed in female than in male (Callahan et al., 2001) In experimental models aged female animals are more sensitive to kainic acid. Thus, females show increased hippocampal neurodegeneration, enahanced astrocyte proliferation and higher levels of BDNF in hippocampus (Zhang et al., 2008)

4 GENDER DIFFERENCES IN PARKINSON S DISEASE The incidence is greater in men than in women (Benito-Leon et al., 2003; de Lau et al., 2004; Van Den Eeden et al., 2003; Wooten et al., 2004). Course and symptoms as well as pharmacological treatment are also gender different (Fernandez et al., 2000; Haaxma et al., 2007; Homann et al., 2003; Martinelli et al., 2003; Zappia et al., 2005). Women tend to be older than men at symptom onset and present more often than men a tremor dominant form of disease, which in turn is associated with a slower disease progression. Moreover, at onset of the disease they have higher levels of striatal dopamine binding than men (Haaxma et al., 2007).

5 GENDER DIFFERENCES IN EXPERIMENTAL MODEL OF PARKINSON S DISEASE In mice model, male animals show a stronger depletion of dopamine after intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) than female animals (Czlonkowska et al., 2006). Inflammatory processes could have a role in this gender dependent event. Namely, different gene expression profiles of pro-inflammatory molecules, such as TNF, IL-6, IFN, IL-1, occur in male and female animals after MPTP injection (Czlonkowska et al., 2006).

6 SEX DIFFERENCES IN MULTIPLE SCLEROSIS Multiple Sclerosis is more frequent in female than in male (ratio 2:1) (Noonan et al., 2002; Houzen et al., 2003; Orton et al., 2006; Schwendimann and Alekseeva, 2007 ) The disease mainly affects young and postpubertal women and most commonly causes relapsing-remitting-type symptomatology. Therefore, women showing a benign course (Hawkins and McDonnell, 1999) Men have a worse prognosis. Indeed, they are affected in older age and develop a more severe pathology, defined as a shorter time to reach severe disability (Confavreux et al., 2003)

7 SEX DIFFERENCES IN SCHIZOPHRENIA The risk is comparable, but sex differences occur in age of onset and in course of the disease as well as in the response to treatment (Hafner, 2003; Halbreich & Kahn, 2003; Rao and Kolsch, 2003; Riescher-Rossler & Hafner, 2000) Men usually experience first onset between 15 and 24 years. This is about 3-4 years earlier than in women. A second increase of the incidence occurs only in women between 45 and 54 years. Men show more severe negative symptoms than women. Women react better to antipsychotic therapy than men. Functional (FMR) and morphometric studies show sex differences.

8 SEX DIFFERENCES IN AUTISM Clinical and epidemiological studies indicate that boys are affected more frequently than girls (ratio 4:1) (Fombonne, 1999, 2003;Volkmar et al., 1993) Male heterozygous reeler, at variance with female, have a reduced number of Purkinje cells (Doulazmi et al., 1999; Hadj-Sahraoui et al., 1996; Biamonte et al., 2009)

9 WHAT CAUSES PERIPHERAL NEUROPATHY? Physical injury (trauma) Systemic diseases: Diabetes mellitus Kidney disorders Hormonal imbalances Vitamin deficiences Alcoholism Vascular damage and blood diseases Connective tissue disorders and chronic inflammation Cancers and benign tumors Repetitive stress Toxins Infections and autoimmune disorders Inherited forms of peripheral neuropathy

10 GENDER DIFFERENCES IN DIABETIC NEUROPATHY Diabetic neuropathy is more frequent in men than in women (Basit A. et al., 2004; Booya F. et al, 2005) Males develop neuropathy approximately 4 years earlier than females (Aaberg M.L. et al., 2008) Neuropathic pain and negative sensory symptoms are more frequent in female, whereas atrophy is more frequent in male patients (Kiziltan M.E. & Benbir G., 2008) Motor nerve conduction abnormalities and ulnar nerve involvement is also more frequent and severe in males (Albers J.W. et al, 1996; Kiziltan M.E. et al., 2007; Kiziltan M.E. & Benbir G., 2008)

11 NEUROSTEROIDS PARACRINE AUTOCRINE ENDOCRINE STEROID HORMONES

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13 O 5 -reductase O Progesterone O 3 -hydroxysteroiddehydrogenase O H 5 -pregnan-3,20-dione (dihydroprogesterone, DHP) O HO H 5 -pregnan-3 -ol-20-one (tetrahydroprogesterone, THP)

14 OH O Testosterone 5 -reductase OH 3 -hydroxysteroiddehydrogenase O H OH 5 -androstan-17 -ol-3-one (dihydrotestosterone, DHT) HO H 5 -androstan-3,17 -diol (3 -diol)

15 CLASSICAL AND NON CLASSICAL STEROID RECEPTORS PROGESTERONE RECEPTOR ANDROGEN RECEPTOR ESTROGEN RECEPTOR GLUCOCORTICOID RECEPTOR MINERALOCORTICOID RECEPTOR GABA-A RECEPTOR GABA-B RECEPTOR NMDA RECEPTOR AMPA RECEPTOR KAINATE RECEPTOR SIGMA 1 RECEPTOR

16 Are gender differences in neurodegenerative disorders related to neuroactive steroids?

17 In female rats, the fluctuation in hormonal levels during estrous cycle affects the response of the brain to pathological insults. For instance, neurotxic effect of kainic acid on hippocampus of intact females rats is different depending on the day of the estrous cycle on wich the neurotoxin is injected (azcoitia et al. 1999). Morning of estrous (i.e. 1 days after the peak of estrogen) No neuronal loss Morning of proestrus (when peak of estrogen occurs). Loss of neurons Ovariectomized rats..loss of neurons

18 In premenopausal women parkinsonian symptoms have been reported to worsen at the onset of menses, when estrogen levels are low (Quinn & Marsden 1986). Postmenopausally hormone replacement therapy has been reported to improve symptoms (Saunders-Pullman et al. 1999), with a worsening on withdrawal of treatment (Sandyk 1989). Women who underwent oophorectomy before the onset of menopause had increased risk of parkinsonism compared with referent women and he risk increased with younger age at oophorectomy (Rocca et al, 2008).

19 MULTIPLE SCLEROSIS (EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS) SEX STEROIDS MENSTRUAL CYCLE PREGNANCY MENOPAUSE

20 ASSESSMENT OF NEUROACTIVE STEROIDS BY LIQUID CHROMATOGRAPHY TANDEM MASS SPECTROMETRY

21 PREG PROG DHP SPINAL CORD CEREBELLUM CORTEX SCIATIC NERVE PLASMA = = = = THP Isopregnanolone = = T DHT u.d.l 3α-diol = DHEA 17β-estradiol = = = = = u.d.l

22 5 score immunization 1 0 acute remission relapse Dark-Agouti rat

23 score/section (6) * (6) M EAE F EAE

24 EFFECT OF EAE ON NEUROACTIVE STEROID LEVELS SPINAL CORD PLASMA PREGNENOLONE PROGESTERONE DIHYDROPROGESTERONE TETRAHYDROPROGESTERONE ISOPREGNANOLONE TESTOSTERONE DIHYDROTESTOSTERONE 3ALPHA-DIOL

25 ISOPREGNANOLONE DHP GABA-A receptor PROG receptor THP

26 DHT 3ALPHA-DIOL AR GABA-A receptor ER BETA

27 EFFECT OF DIABETES ON NEUROACTIVE STEROID LEVELS SCIATIC NERVE PREGNENOLONE PROGESTERONE DIHYDROPROGESTERONE TETRAHYDROPROGESTERONE ISOPREGNANOLONE TESTOSTERONE DIHYDROTESTOSTERONE 3ALPHA-DIOL

28 pg/mg tissue pg/mg tissue pg/mg tissue pg/mg tissue pg/mg tissue pg/mg tissue pg/mg tissue pg/mg tissue M WT WT PREG F M HZ F M # WT 3β, 5α THP T # 3 2 < LOQ < LOQ 1 < LOQ M F M F 0 M F M F HZ LOQ, limit of quantification # P < 0.01 P < WT PROG F M HZ # HZ M M F WT F < LOQ F DHP M DHT M HZ F F M WT WT HZ WT HZ M 3α, 5α THP F 3α-diol F M M # HZ < LOQ < LOQ < LOQ < LOQ F F

29 pg/mg tissue pg/mg tissue LEVELS OF NEUROACTIVE STEROIDS IN MALE CEREBELLUM pg/mg tissue pg/mg tissue * ** TESTOSTERONE * *** DHT /+ rl/+ +/+ P5 P15 rl/+ 0 +/+ rl/+ +/+ P5 P15 rl/+ 0.4 * 0.25 ** *** α-DIOL β-DIOL 0.1 +/+ rl/+ +/+ P5 < LOQ < LOQ P15 rl/ /+ rl/+ +/+ P5 P15 rl/+

30 pg/mg tissue pg/mg tissue LEVELS OF NEUROACTIVE STEROIDS IN FEMALE CEREBELLUM pg/mg tissue pg/mg tissue 0.08 TESTOSTERONE 12 8 DHT /+ rl/+ +/+ P5 P15 rl/+ 0 +/+ rl/+ +/+ P5 P15 < LOQ rl/ α-DIOL 0.4 * 17β-DIOL /+ rl/+ +/+ P5 P15 rl/ /+ rl/+ +/+ P5 P15 rl/+

31 TESTOSTERONE DHT 17β-Estradiol

32 A WORKING MODEL OF PBR FUNCTION CHOLESTEROL PREGNENOLONE CHOLESTEROL This step of trasporting cholesterol from cytoplasm into the inner mitochondrial membrane is the primary point of control in the acute stimulation of steroidogenesis DBS VDAC PBR Outer mitochondrial membrane ADC PREGNENOLONE Inner mitochondrial membrane P450scc: cytochrome P450side-chain cleavage. VDAC: voltage-dependent anion channel BDS: benzodiazepine-binding site ADC: adenine nucleotide carrier Steroid synthesis

33 CONCLUSIONS -The levels of neuroactive steroids present in male and female CNS are different in control animals and differently affected by pathology. -These modifications may affect the result of therapy based on neuroactive steroids and may suggest new therapeutic strategies. -The findings here reported may represent an important background for new sex oriented therapy neuroactive steroid-based for neurodegenerative disorders.