Small dose of L-dopa/Benserazide hydrochloride improved sepsis-induced neuroinflammation and long-term cognitive dysfunction in sepsis mice

Li, Fan; Zhang, Bin; Duan, Shangchun; Wang, Qing; Tan, Longjiao; Chen, Shanshan; Wang, Yi; Li, Dan; Yang, Jing; Tong, Jianbin; Fang, Jiakai; Yuan, Long

doi:10.1016/j.brainres.2020.146780

Cited by 17 publications

(8 citation statements)

References 41 publications

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“…TDCA ameliorates systemic inflammation, normalizes blood pressure, prevents kidney injury, and prolongs survival in a mouse sepsis model ( 65 ). DOPA has anti-neuro inflammation effects and improved neuroplasticity in septic mice ( 66 ). The plasma of the WT-CLP group showed also increased levels of isoforms of the phospholipids species lysophaphatidylserine and PS, probably due to their procoagulant activity in sepsis ( 67 , 68 ).…”

Section: Discussionmentioning

confidence: 99%

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

et al. 2020

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We previously reported the Bruton's tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib improve outcomes in a mouse model of polymicrobial sepsis. Now we show that genetic deficiency of the BTK gene alone in Xid mice confers protection against cardiac, renal, and liver injury in polymicrobial sepsis and reduces hyperimmune stimulation (“cytokine storm”) induced by an overwhelming bacterial infection. Protection is due in part to enhanced bacterial phagocytosis in vivo , changes in lipid metabolism and decreased activation of NF-κB and the NLRP3 inflammasome. The inactivation of BTK leads to reduced innate immune cell recruitment and a phenotypic switch from M1 to M2 macrophages, aiding in the resolution of sepsis. We have also found that BTK expression in humans is increased in the blood of septic non-survivors, while lower expression is associated with survival from sepsis. Importantly no further reduction in organ damage, cytokine production, or changes in plasma metabolites is seen in Xid mice treated with the BTK inhibitor ibrutinib, demonstrating that the protective effects of BTK inhibitors in polymicrobial sepsis are mediated solely by inhibition of BTK and not by off-target effects of this class of drugs.

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Section: Discussionmentioning

confidence: 99%

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

et al. 2020

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“…These regimens mediate some cognitive impairment. l -Dopa has been shown to improve performance in some cognitive disorders (Wang et al ., 2017; Li et al ., 2020), so this drug was used in the present study to evaluate its effect on temozolomide-induced cognitive impairment using some behavioral cognitive tests, histological and molecular analysis in the mouse hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Effect of l-Dopa in acute temozolomide-induced cognitive impairment in male mice: a possible antineuroinflammatory role

Salarinejad¹,

Esmaeilpour²,

Shabani³

et al. 2023

Behavioural Pharmacology

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Temozolomide is used commonly in the treatment of some types of cancers, but it may also result in cognitive impairments such as memory deficits. l-Dopa, a well known medicine for the central nervous system, has been shown to have positive effects on some cognitive disorders. Here we sought to investigate the effect of l-Dopa on temozolomide-induced cognitive impairments. BALB/c mice were subjected to 3-days temozolomide and 6-days concomitant l-Dopa/benserazide administration in six groups (control, l-Dopa 25 mg/kg, l-Dopa 75 mg/kg, temozolomide, temozolomide + l-Dopa 25 mg/kg, and temozolomide + l-Dopa 75 mg/kg). Open field test, object location recognition, novel object recognition test, and shuttle-box test were carried out to determine the locomotor, anxiety-like behavior, and memory function of subjects. TNF-α and brain-derived neurotrophic factor (BDNF) gene expression in the hippocampus was measured by real-time PCR. Mice treated with temozolomide showed recognition memory impairment, along with hippocampal TNF-α and BDNF mRNA expression level raise, and detection of histological insults in hematoxylin and eosin hippocampal slides. Mice that received temozolomide + l-Dopa showed normal behavioral function and lower TNF-α and BDNF hippocampal mRNA expression levels, and histologically normal hippocampal CA1 region in comparison with mice in the temozolomide group. Our results provide evidence that l-Dopa prevents temozolomide-induced recognition memory deficit in mice at the acute phase probably via l-Dopa antineuroinflammatory effects.

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“…A recent study reported decreased dopamine levels in the hippocampus after CLP, which was associated with lower discrimination index in the object recognition test 12 days later and increasing escape latency ain the Barnes maze test 14 days later (102). However, intraperitoneal administration of L-dopa/ Benserazide hydrochloride (L-DA) overtly reduced the percentage of activated microglia in hippocampus.…”

Section: Neurotransmitter Dysfunctionmentioning

confidence: 99%

“…The authors also found that the L-DA's inhibition of microglial activation was abolished when dopamine D1 receptor antagonist was added. However, it should be noted that L-DA was effective only when it was applied in the acute phase of sepsis (102). Moreover, significant dopamine D4 receptor loss was also reported in mice suffering from cognitive impairment in a CLP model while agonism of D4 was sufficient to rescue cognitive abnormalities (103).…”

Section: Neurotransmitter Dysfunctionmentioning

confidence: 99%

Current Understanding of Long-Term Cognitive Impairment After Sepsis

Liu

Yang

2022

Front. Immunol.

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Sepsis is recognized as a life-threatening multi-organ dysfunction resulting from a dysregulated host response to infection. Although the incidence and mortality of sepsis decrease significantly due to timely implementation of anti-infective and support therapies, accumulating evidence suggests that a great proportion of survivors suffer from long-term cognitive impairment after hospital discharge, leading to decreased life quality and substantial caregiving burdens for family members. Several mechanisms have been proposed for long-term cognitive impairment after sepsis, which are not mutually exclusive, including blood-brain barrier disruption, neuroinflammation, neurotransmitter dysfunction, and neuronal loss. Targeting these critical processes might be effective in preventing and treating long-term cognitive impairment. However, future in-depth studies are required to facilitate preventive and/or treatment strategies for long-term cognitive impairment after sepsis.

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Small dose of L-dopa/Benserazide hydrochloride improved sepsis-induced neuroinflammation and long-term cognitive dysfunction in sepsis mice

Cited by 17 publications

References 41 publications

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

X-Linked Immunodeficient Mice With No Functional Bruton's Tyrosine Kinase Are Protected From Sepsis-Induced Multiple Organ Failure

Effect of l-Dopa in acute temozolomide-induced cognitive impairment in male mice: a possible antineuroinflammatory role

Current Understanding of Long-Term Cognitive Impairment After Sepsis

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