| Part oneReview of literature Stroke,as a common condition affecting the elderly,has tremendous and life-threatening implications.Post-stroke depression,characterized by the combination of a stroke event and depression,can lead to devastating results with significant limitations,increased mortality,and poor quality of life.As a common complication of stroke,its incidence fluctuates between 20% and 40%.In light of its implications in patient outcomes,understanding the complex interconnection between these two conditions might prove vital for more appropriate care for such subjects.From the first mention of the notion of Post-stroke depression to today,researchers have been working tirelessly to identify specific biomarkers and the involved mechanisms for a better and early diagnosis of the condition.To date,it is established that the incidence of post-stroke depression is closely connected with several parameters such as the location of the stroke lesion,the degree of neurological deficit,neuronal remodeling,abnormal glutamate circulations,and neuroinflammation.Brain regions such as the prefrontal cortex,limbic system,amygdala,and habenula are responsible for mood regulation and cognition in mammals.Imaging studies have found that depressed subjects have reduced volume of marginal brain regions such as the hippocampus where,neuronal atrophy,decreased number and density of spinous and long dendrites,as well as synaptic dysfunctions have been observed.Additionally,previous studies performed on animal models have confirmed that abnormal glutamate circulation affects synaptic remodeling in the hippocampus and participates in post-stroke depression occurrence.Recently more attention has been directed toward identifying the involvement of imagingrelated biomarkers as well as neural circuits to aid in an early diagnosis.But a lot remains to be done since it is still in its infancy and is challenged by technical limitations.In this section,we will review the current status of post-stroke depression-related works from the pathophysiological,diagnostic,and treatment point of view,as well as current attempts at new therapeutic options.Part two Antidepressant properties of ketamine in post-stroke depression models: the role of the NMDAR/CaMKⅡ pathwayBackground: Depression has been a serious yet underestimated complication of stroke.Yet,the pathophysiology of post-stroke depression and adapted treatment options have been lacking and need further study.Previous studies have shown that Ketamine,an N-methyl-Daspartate receptor(NMDAR)antagonist,possesses rapid and lasting antidepressant properties.However,the mechanisms and efficacy of ketamine on post-stroke depression remain to be studied.Methods: To investigate these mechanisms,a post-stroke depression model comprised of a combination of permanent focal cerebral ischemia model commonly referred to as middle cerebral artery occlusion(MCAO)and chronic unpredictable mild stress(CUMS)models was performed on Sprague Dawley rats.Ketamine was then injected within the left hippocampal dentate gyrus of the treatment group.The sucrose preference test and several open field test parameters were analyzed to assess ketamine’s efficacy.Additionally,quantification methods were used to evaluate and measure changes in NMDAR2 A,NMDAR2B,NMDAR1,NMDAR3,and their downstream targets CaMK2 A and CaMK2 B gene and protein expressions after ketamine intervention.Results: The results show that CUMS led to a significant decrease in sucrose preference among stress MCAO rats(p < 0.05).This finding is further supported by the open field test results indicating that MCAO rats subjected to CUMS had a significantly longer immobility time,shorter traveled distance,and slower average speed than their non-CUMS counterparts(p < 0.05).The post-treatment results,however,showed that ketamine administration significantly increased sucrose consumption and preference among treated MCAO+CUMS subjects as compared to their non-treated counterparts(p < 0.05).The post-treatment open field test results further indicated that treated MCAO+CUMS rats showed significant improvements in rearing counts,immobility,average speed,and distance traveled(p < 0.05).The results also showed that treated rats exhibited significant improvements in exploratory behaviors,as shown by a significantly longer time spent in the central zone than non-treated one(p < 0.05).The protein quantification analysis results showed that MCAO+CUMS rats treated with ketamine exhibited significant downregulation of the NMDAR2 A variant as early as 1 hour after injection,an effect that lasted for approximately 2hours(p < 0.05).The opposite effect was observed with the NMDAR2 B variant with significant upregulation of its expression 1 hour after ketamine treatement(p < 0.05).However,not all NMDAR subunits were impacted by ketamine’s effects.Indeed,assessments of the NMDAR1 and NMDAR3 showed that ketamine did not have a significant on those two variants(p > 0.05).We proceeded to evaluate ketamine’s impact on the two CaMKII subunits.The findings showed that ketamine led to a significant downregulation of both CaMK2 A protein expression and transcription as early as 1 hour after administration(p < 0.05).The effect lasted for approximately 2 hours(p <0.05),with regular levels seen 4 hours after treatment(p > 0.05).CaMK2 B results,however,showed that ketamine significantly upregulated its transcription and expressions(1 hour after administration and up to 2 hours,p < 0.05)in treated subjects,an effect that lasted less than 4 hours after treatment(p > 0.05).Analysis of the phosphorylated version of the two subunits showed that ketamine led to a significant activation of the CaMK2 A variant and deactivation of the CaMK2 B subunit(p < 0.05).The results also showed that such effects were rapid and lasted for approximately 2 hours(p <0.05).Conclusions: These findings not only suggest that ketamine represents a promising candidate for the treatment of post-stroke depression but also that ketamine’s rapid antidepressant effects might be achieved through selective modulation of the NMDAR/CaMKⅡ subunits in key brain regions.Part three Ketamine-mediated synaptic remodeling of the dentate gyrus in post-stroke depression models: the role of the NMDAR/CaMKⅡpathwayBackground: Synaptic remodeling plays a significant role in the pathophysiological processes of depressive conditions such as post-stroke depression.This is evidenced by our previous findings implicating hippocampal synaptic remodeling in the occurrence of poststroke depression.Yet,whether ketamine’s lasting antidepressant and behavioral changes properties in post-stroke depression models are linked with hippocampal synaptic remodeling remains to be determined.Methods: A post-stroke depression model comprised of MCAO and CUMS was performed on the study subjects.Ketamine was then injected within the hippocampal dentate gyrus of the treatment group.Expressions of remodeling-related proteins MAP2,NFL,PSD95,and SYN were measured.Additionally,changes in NMDAR2 A,2B,CaMK2 A,and 2B,expressions as well as their association with PSD95 in the hippocampal CA1,CA3 and DG regions were detected and analyzed through protein quantification,immunofluorescence staining,and confocal microscopy.Synaptic ultrastructural changes in the dentate gyrus were observed through electron microscopy.Results: The post-treatment results showed that MCAO+CUMS rats treated with ketamine exhibited a significant decrease in NR2A/NR2 B ratio than their non-treated counterparts(p <0.05),an effect that lasted for more than 4 hours after ketamine administration(p < 0.05).Ketamine-treated MCAO+CUMS rats had significant and rapid upregulation of PSD95(1hour and 2 hours after ketamine treatment)as well as NFL(4 hours after administration)protein expressions(p < 0.05).While MAP2 and Synaptophysin expressions did not vary significantly(p > 0.05).The colocalization analysis of NMDAR2 A,2B,CaMK2 A,and 2B with PSD95 within the CA1,CA3,and DG regions of the hippocampus showed that ketamine intervention had no significant effects on NMDAR2 A and CaMK2 A colocalization with PSD95 within all assessed hippocampal regions(p > 0.05),nor did it have an impact on NMDAR2B colocalization with PSD95 within the CA1 and CA3 of the hippocampus(P >0.05).However,in the DG region,the analysis showed that treated MCAO+CUMS rats had significantly lower Pearson’s correlation coefficients(reflective of NMDAR2 B colocalization with PSD95)1 hour after the intervention compared to their non-treated counterparts(p < 0.05).An effect that lasted for 4 hours(p < 0.05).While the colocalization correlation of CaMK2 B with PSD95 increased significantly within the same region 1 hour after the intervention(P < 0.05)and lasted for 4 hours(P < 0.05).The ultrastructural analysis under electron microscopy showed significant synaptic morphological changes within the hippocampal dentate gyrus of MCAO+CUMS rats 24 hours after ketamine treatment.Those changes included a significant extension of the postsynaptic dense area,a significant increase of synaptic density and thickness(P < 0.05),and a narrowing of synaptic width(P < 0.05),changes that lasted more than 7 days after ketamine administration(P < 0.05).Conclusions: These findings not only indicate that ketamine’s lasting antidepressant effects might be mediated by its induction of synaptic plasticity and remodeling in key brain regions such as the hippocampal dentate gyrus,but also that the process is achieved through modulation of the NMDAR/CaMKII pathway,therefore,accounting for the rapid and lasting effects. |
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