## 4 Discussion  
Although Cis is a potent chemotherapeutic drug, it has many harmful complications. In the existing study we focused on the toxic effect of Cis on the brain; the main target of Cis. It crosses the BBB and inhibits the proliferation of neuronal stem cells [3]. During Cis therapy, a marked decrease in the hippocampus neurons number has been identified [49]. Our results showed that Cis causes severe cerebral damage which is manifested by a significant increase of CHE and GGT activities in the Cis group in comparison with the control group. These findings are in agreement with [50; 51; 52]. References [53; 54] reported that GGT is posited as an early and a delicate marker for brain damage. CHE is an important enzyme involved in acetyl choline catabolism at cholinergic synapses into acetic acid and choline [55]. Also, CHE is considered a target enzyme for Cis induced cerebral damage as the inhibition of CHE activity leads to the disturbance of the neurotransmitter acetylcholine [56] and an obvious disturbance in the nerve impulse transmission will take place [57]. Treatment with _Ginkgo_ significantly reduced CHE and GGT activities compared to the Cis group. This effect might be explained by the efficacy of _Ginkgo_ to scavenge the free radicals and suppress the leakage of enzymes through plasma membranes [58]. Figure 6: The changes of DNA fragmentation% in different groups. The effect of Cis, _Ginkgo_, and their combination on the expression level of DNA fragmentation% in rat brain tissues. Data present as mean \(\pm\) SE (\(n=10\)). a indicates a significant difference compared to control group, b indicates a significant change compared to Cis group. a and b indicate statistical significance at \(p<0.05\) using ANOVA followed by Tukey–Kramer as a post ANOVA test. Furthermore, our results showed that Cis causes severe cerebral oxidative stress which is revealed by the severe depletion of GSH concentration [59], SOD activity, TAC with a concurrent augmentation of MDA. These findings are in accordance with [60]. Stimulation of lipid membrane peroxidation via augmentation of free oxygen radicals generation together with down regulation of antioxidant defense could explain the oxidative harmful effects of Cis [61]. Based on the existing work, the potent antioxidant outcome of _Ginkgo_ on Cis-stimulated cerebral oxidative stress was so clear and could be inferred by the significant reduction of MDA [62] and increase in cerebral antioxidant defense GSH and SOD [63]. The antioxidant properties of _Ginkgo_ are related to its efficacy to work as a free radical scavenger by preventing the lipid peroxidation [58]. The bio-flavonoid contents of _Ginkgo_ have the upper hand in its antioxidant properties [64] through the direct scavenging effect on ROS, removing pro-oxidant transitional metal ions and boosting antioxidant proteins [65]. Apoptosis, which is clarified as a programmed cell death, controls cell repair and the removal of injured cells [66]. Cis induces neuronal loss by promoting neuronal apoptosis and inhibiting neurogenesis [67]. A novel finding is the ability of Cis to increase the production of APP and accumulation of A\(\beta\), which is generated by proteolytic processing of the APP via \(\beta\)-secretase (\(\beta\)-amyloid cleavage enzyme) and \(\gamma\)-secretase complex [68]. Over accumulation of A\(\beta\) is one of the most acceptable hypotheses explaining the induction of neuronal oxidative damage and cell expiration in Alzheimer's disease (AD) [15; 69; 70]. The neuronal apoptosis of AD is distinguished by the presence of many apoptotic markers which are found in the brains of AD sufferers after death, such as inducing caspase activities and DNA fragmentations [71; 72]. Based on our findings, Cis increases the expression of some purinergic receptors such as P2Y12R and P2X7R. It is recorded that purinergic receptors significantly increased the neurotoxicity [73]. They are implicated in several CNS disorders, such as neuronal damage [74] and Alzheimer's disease [75].