Streptozotocin-induced diabetes in rodents appears to be the most
suitable animal model because it reflects the symptoms of diabetes in human (King, 2012) and it is
characterized by severe loss in body weight (Al-Roujeaie et al., 2016), and
this is also reflected in the present study. The decreases in body and testis
weight in diabetic rats showed the loss or degradation of structural proteins
due to diabetes and a significant reduction in the serum levels of
the main androgenic hormone, testosterone (Roy et
al., 2014). NG treatment enhanced the testicular weight.
Recently, Al-Roujeaie and his colleagues (2016) reported
that, rutin a phenolic compound enhanced the testicular weight of STZ-induced
diabetic rats and enhanced the sexual behavioral activity. This may consider
that phenolic compounds have ability to enhance the testicular weight which
further justified with present results.

 

In present study, sever sexual impairment was found in STZ-induced
diabetic rat by inhibiting the EL, PEI, ML and IL latencies and increasing the
MF and IF frequencies.  Our
observations are in agreement with earlier reports showed fewer in sexual
behaviors of diabetic animals compared controls (Scarano et al., 2006;
De et al., 2016). In NG supplemented diabetic rats, we found improvement
in all the behavioral parameters that suggests the drug produces beneficial
effect in one of the diabetic-induced complication. It is well established that
the TTT levels decreases in diabetic conditions. However, this factor alone
does not appear responsible for changes in mating behavior as testosterone
replacement did not reverse the adverse effects of diabetes on sexual behavior.
While STZ-induced sexual dysfunction might be due to reduced testosterone responsiveness,
it seems likely that ED in the diabetic state results from direct or indirect
action of insulin and/or glucose on the adrenergic complex (Kniel et al.,
1986). Our results also showed significant decrease in serum testosterone
levels compared to controls.

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It is well known that penile erection depends on decreased penile
vascular resistance, which subsequently results in increased penile blood flow.
The action consists of the relaxation of the penile helicine arteries and the
cavernous smooth muscle that lines the cavernosal spaces (Andersson and Wagner,
1995). It has demonstrated that reduced vasorelaxation or increased
vasoconstriction under diabetic conditions accounts for the development of ED. As previously reported, the rats showed evidence of declining
erectile function following the STZ injection (Choi et al., 2012). When
Choi and his colleagues (2012) compared to the age-matched controls, the
diabetic rats showed a significant decrease in the ICP/MAP and AUC at the eight
and twelve week assessments after the STZ injection, respectively. Present
results also showed similar decline in ICP/MAP ratio in diabetic rats compared
to normal healthy animals. The NG treatment markedly improved in ICP/MAP ratio
compared to untreated diabetic rats.  
Furthermore, our results are more consistent with those from Melman et
al, (2009) which have reported significant changes in ICP/MAP in as early
as 1 month after STZ injection. The necessity for other indices in addition to
the ICP/MAP has been suggested by others. Earlier, Zhang and his
colleagues (2011) studied such phenolic compound QT on intracavernous pressure
(ICP) of STZ-induced diabetic rats and clearly documented the potential effect
of QT against ED.

 

Hyperglycemia-induced
sexual dysfunction might be due to the inhibition of testosterone, in diabetic
state results from direct or indirect action of insulin and/or glucose on the
adrenergic complex (Kniel
et al., 1986). Present results also showed significant decrease
in serum testosterone levels compared to controls. The NG treatment markedly
increased the inhibited testosterone levels in our diabetic rats which showed
potentials of NG against diabetic-induced ED. Earlier reports documented that,
diabetes causes inhibition in sperm count, motility and viability (Scarano et al., 2006),
similar changes have noted in present study. The decreased values of sperm
numbers, motility and viability were significantly enhanced by the NG treatment.
It supports the beneficial effect of NG against diabetic-induced ED.

 

The pathophysiologic mechanism of diabetic-induced ED
includes both the functional and structural impairment. Endothelial
dysfunction, coordination disorder of the relaxation and contraction of
corporal smooth muscles via the NO/cGMP pathway and the RhoA/Rho-kinase (ROCK)
pathway, autonomic neuropathy and apoptosis in corporal smooth muscles were
simultaneously happened. These processes do not work independently; diverse
combinations of each pathologic mechanism may manifest as DM progresses (Maiorino et al., 2014; Hadi and Suwaidi, 2007; Cho et al.,
2011). Therefore, to prevent and reinstate the
endothelial function of the corpus cavernosum before progression of the
irreversible changes is the best treatment option to overcome diabetic-induced ED. Indeed, the role of oxidative
impairments in the male reproductive system has been suggested in several
experimental studies (Agbaje et al.,
2007; Shrilatha, and Muralidhara, 2007; Amaral et al., 2006). Induction of lipid peroxidation
process and elevation of its biomarker like TBARS in the testicular tissues was
shown to have fundamental implications on testicular physiology and sperm function (Agarwal and Said, 2005). DM is
well known to be strongly correlated with oxidative stress leading to
production of free radicals and act as intercellular second messengers that can
induce activation downstream signaling of many molecules, including transcription
factors like nuclear factor kappa B (NF-?B). These NF-?B and other
transcription factors mediate vascular smooth muscle cell growth and migration
as well as the expression of pro-in?ammatory cytokines such as TNF-?, IL-1?,
and IL-6 (Touyz, 2004). These elevated
pro-in?ammatory mediators antagonize insulin action because of their ability to
augment insulin receptor substrate phosphorylation, leading to insulin
resistance (Senn et al., 2003). Therefore, attenuation of free radical induced NF-?B translocation
and ameliorating oxidative stress in diabetic rats explains an associative
relationship between the in?ammatory cytokines and DM. In the present study,
also found an elevation in the levels of pro-inflammatory and oxidative stress
biomarkers. Such as TNF-?, IL-1? and IL-6 were markedly elevated in the
diabetic group of animals. NG treatment to diabetic rats found inhibition in
pro-inflammatory biomarkers. These findings show the anti-inflammatory
potential of NG which earlier, Lin and Lin, (2011),
reported the anti-inflammatory
effect NG was
in primary mouse splenocytes in the absence or presence of lipopolysaccharide
(LPS) and it showed strong anti-inflammatory activity. In
addition, a beneficial systemic effect of NG on diabetic rats observed by
lowering fasting glucose and enhanced insulin levels in the serum of diabetic
rats. Similar systemic effects of NG on experimentally induced diabetes were
reported in earlier studies also (Hasanein and Fazeli, 2014; Annadurai et al.,
2012; Al-rejaie et al., 2015).

 

In
present study, cGMP levels in penile tissues of diabetic rats were
significantly inhibited. Similar cGMP inhibition was seen earlier in
experimentally-induced diabetic animal’s penile tissue (Yang et al., 2008). Indeed,
the role of oxidative impairments in the male reproductive system
has been suggested in several experimental studies (Agbaje et al., 2007; Amaral et al.,
2006; Shrilatha and Muralidhara, 2007). It is known that hyperglycemia induced increases in the production
of glycation end-products, reactive oxygen and nitrogen species impair nitric
oxide bioavailability and affect penile tissue, leading to changes in
endothelium-dependent vasorelaxation mechanisms (Agarwal et al., 2006). Adenoviral gene transfer of EC-SOD in vivo can reduce corporal
superoxide anion levels and raise cavernosal cGMP levels by increasing NO
bioavailability thus restoring erectile function in the STZ-diabetic rat
(Bivalacqua et al., 2005). The present study determined TBARS and GSH
levels and SOD, CAT, GST and GPx activities as a marker for oxidative stress in
testicular cells. Decreased GSH levels, SOD, CAT, GST and GPx activities and
elevated levels of TBARS were found in STZ-diabetic rats compared with that in
normal controls. In addition, this abnormality in diabetic rats was
significantly restored by NG treatment in dose dependent manner. Earlier
reports revealed that NG has antioxidant potentials (Jagetia and Reddy, 2002; Al-Rejaie et al., 2015). This
suggests that NG treatment could improve ED in diabetic rats partly by
restoring the enzymatic activities and inhibiting oxidative stress in
testicular cells.

 

In
summary, we found that diabetic rats exhibited decreased sexual performance,
ICP levels and ICP/MAP ratio, sperm count inhibition with low motility,
viability, reduced levels of enzymatic activities including SOD, CAT, GST and
GPx, as well as elevated levels of TBARS and inhibited GSH levels in testicular
cells. Treatment with NG markedly corrected these diabetic-induced changes in
mostly dose dependent manner. Finally, could conclude that NG supplementation
may improve the diabetic-induced testicular oxidative stress, inflammation and
that can make improvement in sexual performance. Further preclinical research
into the utility of NG treatment may indicate its usefulness as a valuable
therapeutic approach in ED.

 

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