Streptozotocin-induced diabetes in rodents appears to be the mostsuitable animal model because it reflects the symptoms of diabetes in human (King, 2012) and it ischaracterized by severe loss in body weight (Al-Roujeaie et al., 2016), andthis is also reflected in the present study. The decreases in body and testisweight in diabetic rats showed the loss or degradation of structural proteinsdue to diabetes and a significant reduction in the serum levels ofthe main androgenic hormone, testosterone (Roy etal., 2014). NG treatment enhanced the testicular weight.Recently, Al-Roujeaie and his colleagues (2016) reportedthat, rutin a phenolic compound enhanced the testicular weight of STZ-induceddiabetic rats and enhanced the sexual behavioral activity.
This may considerthat phenolic compounds have ability to enhance the testicular weight whichfurther justified with present results. In present study, sever sexual impairment was found in STZ-induceddiabetic rat by inhibiting the EL, PEI, ML and IL latencies and increasing theMF and IF frequencies. Ourobservations are in agreement with earlier reports showed fewer in sexualbehaviors of diabetic animals compared controls (Scarano et al., 2006;De et al., 2016). In NG supplemented diabetic rats, we found improvementin all the behavioral parameters that suggests the drug produces beneficialeffect in one of the diabetic-induced complication. It is well established thatthe TTT levels decreases in diabetic conditions.
However, this factor alonedoes not appear responsible for changes in mating behavior as testosteronereplacement 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 indirectaction of insulin and/or glucose on the adrenergic complex (Kniel et al.,1986). Our results also showed significant decrease in serum testosteronelevels compared to controls. It is well known that penile erection depends on decreased penilevascular resistance, which subsequently results in increased penile blood flow.
The action consists of the relaxation of the penile helicine arteries and thecavernous smooth muscle that lines the cavernosal spaces (Andersson and Wagner,1995). It has demonstrated that reduced vasorelaxation or increasedvasoconstriction under diabetic conditions accounts for the development of ED. As previously reported, the rats showed evidence of decliningerectile function following the STZ injection (Choi et al., 2012). WhenChoi and his colleagues (2012) compared to the age-matched controls, thediabetic rats showed a significant decrease in the ICP/MAP and AUC at the eightand twelve week assessments after the STZ injection, respectively.
Presentresults also showed similar decline in ICP/MAP ratio in diabetic rats comparedto normal healthy animals. The NG treatment markedly improved in ICP/MAP ratiocompared to untreated diabetic rats. Furthermore, our results are more consistent with those from Melman etal, (2009) which have reported significant changes in ICP/MAP in as earlyas 1 month after STZ injection. The necessity for other indices in addition tothe ICP/MAP has been suggested by others.
Earlier, Zhang and hiscolleagues (2011) studied such phenolic compound QT on intracavernous pressure(ICP) of STZ-induced diabetic rats and clearly documented the potential effectof QT against ED. Hyperglycemia-inducedsexual dysfunction might be due to the inhibition of testosterone, in diabeticstate results from direct or indirect action of insulin and/or glucose on theadrenergic complex (Knielet al., 1986). Present results also showed significant decreasein serum testosterone levels compared to controls. The NG treatment markedlyincreased the inhibited testosterone levels in our diabetic rats which showedpotentials 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 spermnumbers, 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 EDincludes both the functional and structural impairment. Endothelialdysfunction, coordination disorder of the relaxation and contraction ofcorporal smooth muscles via the NO/cGMP pathway and the RhoA/Rho-kinase (ROCK)pathway, autonomic neuropathy and apoptosis in corporal smooth muscles weresimultaneously happened. These processes do not work independently; diversecombinations 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 theendothelial function of the corpus cavernosum before progression of theirreversible changes is the best treatment option to overcome diabetic-induced ED. Indeed, the role of oxidativeimpairments in the male reproductive system has been suggested in severalexperimental studies (Agbaje et al.,2007; Shrilatha, and Muralidhara, 2007; Amaral et al., 2006).
Induction of lipid peroxidationprocess and elevation of its biomarker like TBARS in the testicular tissues wasshown to have fundamental implications on testicular physiology and sperm function (Agarwal and Said, 2005). DM iswell known to be strongly correlated with oxidative stress leading toproduction of free radicals and act as intercellular second messengers that caninduce activation downstream signaling of many molecules, including transcriptionfactors like nuclear factor kappa B (NF-?B). These NF-?B and othertranscription factors mediate vascular smooth muscle cell growth and migrationas well as the expression of pro-in?ammatory cytokines such as TNF-?, IL-1?,and IL-6 (Touyz, 2004). These elevatedpro-in?ammatory mediators antagonize insulin action because of their ability toaugment insulin receptor substrate phosphorylation, leading to insulinresistance (Senn et al., 2003). Therefore, attenuation of free radical induced NF-?B translocationand ameliorating oxidative stress in diabetic rats explains an associativerelationship between the in?ammatory cytokines and DM.
In the present study,also found an elevation in the levels of pro-inflammatory and oxidative stressbiomarkers. Such as TNF-?, IL-1? and IL-6 were markedly elevated in thediabetic group of animals. NG treatment to diabetic rats found inhibition inpro-inflammatory biomarkers. These findings show the anti-inflammatorypotential of NG which earlier, Lin and Lin, (2011),reported the anti-inflammatoryeffect NG wasin primary mouse splenocytes in the absence or presence of lipopolysaccharide(LPS) and it showed strong anti-inflammatory activity. Inaddition, a beneficial systemic effect of NG on diabetic rats observed bylowering fasting glucose and enhanced insulin levels in the serum of diabeticrats.
Similar systemic effects of NG on experimentally induced diabetes werereported in earlier studies also (Hasanein and Fazeli, 2014; Annadurai et al.,2012; Al-rejaie et al., 2015). Inpresent study, cGMP levels in penile tissues of diabetic rats weresignificantly inhibited. Similar cGMP inhibition was seen earlier inexperimentally-induced diabetic animal’s penile tissue (Yang et al., 2008). Indeed,the role of oxidative impairments in the male reproductive systemhas 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 productionof glycation end-products, reactive oxygen and nitrogen species impair nitricoxide bioavailability and affect penile tissue, leading to changes inendothelium-dependent vasorelaxation mechanisms (Agarwal et al., 2006). Adenoviral gene transfer of EC-SOD in vivo can reduce corporalsuperoxide anion levels and raise cavernosal cGMP levels by increasing NObioavailability thus restoring erectile function in the STZ-diabetic rat(Bivalacqua et al.
, 2005). The present study determined TBARS and GSHlevels and SOD, CAT, GST and GPx activities as a marker for oxidative stress intesticular cells. Decreased GSH levels, SOD, CAT, GST and GPx activities andelevated levels of TBARS were found in STZ-diabetic rats compared with that innormal controls.
In addition, this abnormality in diabetic rats wassignificantly restored by NG treatment in dose dependent manner. Earlierreports revealed that NG has antioxidant potentials (Jagetia and Reddy, 2002; Al-Rejaie et al., 2015). Thissuggests that NG treatment could improve ED in diabetic rats partly byrestoring the enzymatic activities and inhibiting oxidative stress intesticular cells. Insummary, 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 andGPx, as well as elevated levels of TBARS and inhibited GSH levels in testicularcells. Treatment with NG markedly corrected these diabetic-induced changes inmostly dose dependent manner. Finally, could conclude that NG supplementationmay improve the diabetic-induced testicular oxidative stress, inflammation andthat can make improvement in sexual performance.
Further preclinical researchinto the utility of NG treatment may indicate its usefulness as a valuabletherapeutic approach in ED.