In the present study, tamoxifen, was used to investigate the impact of changes in OXS and BDNF on hyperlocomotion and hippocampus structural changes, in a ketamine-induced model of psychosis in rats. The hippocampus was chosen, since hippocampal over-activation is known to correlate with the severity of symptoms in psychosis [40, 41]. Hippocampal over-activity contributes to the hyperdopaminergic state in the ventral tegmental area and increases dopamine release in the nucleus accumbens [42]. These changes are responsible for the positive symptoms of schizophrenia in humans [43] and hyperlocomotion in rodents. Hyperlocomotion is considered a putative correlate of positive symptoms of psychotic illness in rodents [44, 45] and is considered a primary outcome to assess manic-like behavior [46].

In the present study, chow-fed rats treated with a subanesthetic dose of ketamine, exhibited hyperlocomotion. In pre-clinical studies, low doses of ketamine (5–10 mg/kg) induce antidepressant effects [47]. However, in moderate doses (10–50 mg/kg), ketamine induces hyperlocomotion, impaired cognitive function and cellular dysfunction [30, 31]. Ketamine treatment is reported to induce oxidative stress and an inflammatory response with increase in pro-inflammatory cytokines including TNF alpha [48, 49]. Oxidative stress induces neuroinflammation [50, 51] and activation of microglial cells that increases the release of inflammatory cytokines, reinforcing the effects of oxidative stress on neuronal toxicity [52, 53].

The hyperlocomotion induced by ketamine was associated with histopathological changes in CA3 region of hippocampus together with increase in hippocampal oxidative stress (OXS) and reduction in BDNF in hippocampus tissue.

According to Lin et al. [54], ROS release after central nervous system injury, leads to astrocytes activation and increase in their number, size, and expression of GFAP, thus causing hippocampus structural abnormalities. ROS release following glutamate excitotoxicity has also been reported to be responsible for disappearance of Nissl’s granules in many pathological conditions indicating decreased neuron function [55]. This could explain the impairment and significant decrease in Nissl’s granules detected in the ketamine group compared to control non ketamine group.

In the present work, tamoxifen/ketamine-treated rats displayed a reduction in hyperlocomotion together with moderate improvement in the structure of (CA3) region in the hippocampus. Risperidone/ketamine-treated rats also showed noticeable improvement compared to control ketamine-group. Ketamine-rats treated with risperidone and tamoxifen combination showed a further reduction in hyperlocomotion and more significant improvement in the structure of (CA3) region in the hippocampus compared to control ketamine-group and to the risperidone treated group. This was evident by a significant increase in the Nissl granules content of the pyramidal cells and a significant decrease in immune reactive astrocytes with GFAP, when compared to control ketamine group.

The beneficial effects of tamoxifen on hyper locomotion and hippocampus structure in the ketamine-rats may be related to the reduction in OXS and increase in BDNF, compared to control ketamine-group. These findings are in accordance with previous studies [19, 22] and [23].

The greater improvement in hyperlocomotion and hippocampus structure, in risperidone/tamoxifen/Ketamine treated rats, compared to risperidone/ketamine treated rats, might be related to the greater reduction in OXS and increase in BDNF in risperidone/tamoxifen/ketamine treated rats.

The reduction on OXS and increase in BDNF and the subsequent reduction in hyperlocomotion induced by tamoxifen are probably related to its PKC inhibitory effects [19]. Indeed, excessive activation of PKC has been suggested to be involved in mania [16] via an increase in OXS [56] and a decrease in BDNF [57, 58].

The inhibitory effects of tamoxifen on hyperlocomotor activity are not probably related to its estrogen modulatory effects, since the anti-estrogenic agent clomiphene failed to induce such an effect when given alone and did not enhance the effects of risperidone when combined with it. Similar results were reported by several investigators. Acute and chronic tamoxifen but not clomiphene or medroxyprogestrone blocked methylphenidate-induced hyperlocomotion in mice [26]. Similarly, in a study by Sabioni et al. [33], tamoxifen and chelerythrine (a PKC inhibitor) completely blocked the hyperlocomotion induced by amphetamine, while an intermediate medroxyprogesterone dose partially reduced the amphetamine-induced hyperlocomotion.

In the second part of the study, bone examination revealed that risperidone/ketamine group exhibited marked thinning of bone trabeculae with wide separation and discontinuity of some bone trabeculae with areas of osteolysis. Histomorphometric findings revealed a significant decrease in trabecular bone thickness and percentage of trabecular bone volume. Indeed, risperidone was reported to increase bone resorption and reduce bone formation with elevation of all bone resorption parameters as, number of osteoclasts, osteoclastic surface, and eroded surface, probably due to elevated Rankl expression [59]. The effects of risperidone were more apparent in inner cancellous bone trabeculae than in the outer cortical bone. This is in accordance with Takata and Yasui [60] who reported that bones with high proportion of cancellous bone were at the highest risk of osteoporosis. Wide bone marrow spaces with increased adipocytes were also observed in risperidone/ketamine group and might be attributed to the observed decrease in cancellous bone thickness.

The combination of tamoxifen with risperidone in ketamine treated rats was associated with lesser bone damage compared to risperidone/ketamine group. According to Zhong et al., [61] tamoxifen reduced osteoclast activity and bone turnover in humans, decreased bone resorption, increased femoral trabecular bone formation, increasing trabeculae number and thickness, bone volume with net bone gain at the distal femurs.

The bone damage seen in risperidone/ketamine group might be attributed to the increase in OXS in this group. Increased OXS has been reported to affect bone mineral density [5] and to be involved in the increased risk of bone fractures in patients on antipsychotic agents. [62].

The favorable effects of combination with tamoxifen on bone architecture might be attributed to the reduction in bone OXS seen in the tamoxifen/risperidone/ketamine group compared to risperidone/ketamine group.

An increase in central BDNF in the tamoxifen/risperidone group compared to risperidone alone might have also contributed to the favorable effect of combination with tamoxifen. Central BDNF levels have also been suggested to affect bone mineral density and BDNF receptors have been described in bone [4]. BDNF has been shown to play a role in osteogenesis and to be involved in osteoblast differentiation and in the increased mRNA expression of osteocalcin [63].

Although the estrogenic effect of tamoxifen is expected to be involved in its beneficial effects on bone structure, yet, its PKC inhibitory effects might have also contributed. In fact, PKC inhibition has been reported to block osteoclast functions and bone resorption [64, 65].

The findings of the present study have important implications. The greater reduction in OXS and increase in BDNF seen in the risperidone/tamoxifen treated group, compared to risperidone treatment alone is clinically significant. Risperidone has been reported to induce both pro-oxidative and antioxidative effects [8, 66]. Its effects on BDNF level are also quite inconsistent. Risperidone has been reported to induce, no significant effect, insignificant reduction, or an increase in BDNF level [13,14,15, 67]. Thus, the effects of risperidone on OXS and BDNF might be the net result of its positive and negative effects on OXS and BDNF. Indeed in our study although the effects of risperidone on OXS and BDNF were potentiated by combination with tamoxifen, yet the effects of tamoxifen were not potentiated by combination with risperidone. These findings suggest that the effects of tamoxifen on OXS and BDNF are more consistent than those of risperidone as suggested by other studies.

Hence, combination of tamoxifen with risperidone, may counteract any pro-oxidative effect or reduction in BDNF that might be induced by risperidone, increasing its beneficial behavioral effects while reducing its bone damaging effects.

These results may need to be replicated with other protein C kinase inhibitors and in larger samples and in combination with several toeher anti-psychotics besides risperidone. Measurement of protein C Kinase is a difficult process but will be needed in future studies to confirm the results. The real challenge is the search for a PKc inhibitor which unlike tamoxifen exhibits non-estrogenic properties, since unfortunately TAM is the only PKc inhibitor that can cross the BBB.

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