Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs

Lilius, Tuomas; Blomqvist, Kim; Hauglund, Natalie L.; Liu, Guojun; Stæger, Frederik Filip; Bærentzen, Simone Larsen; Du, Ting; Ahlström, Fredrik; Backman, Janne T.; Kalso, Eija; Rauhala, Pekka

doi:10.1016/j.jconrel.2019.05.005

Cited by 87 publications

(80 citation statements)

References 44 publications

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“…For instance, dexmedetomidine and ketamine enhance CSF influx alongside perivascular spaces [53]. Moreover, similar to what happens during sleep, anesthesia is associated with a substantial increase in both perivascular and extracellular space volume [54]. Thus, it would be interesting to check whether the effects we have observed with TGN-20 persist in awake animals.…”

Section: Plos Onementioning

confidence: 77%

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

Debaker¹,

Djemaï²,

Ciobanu³

et al. 2020

PLoS ONE

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The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its dysfunction might lead to several brain pathologies, including the Alzheimer's disease. A key component of the GS and brain tissue water circulation is the astrocyte which is regulated by acquaporin-4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo and non-invasively.

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Section: Plos Onementioning

confidence: 77%

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

Debaker¹,

Djemaï²,

Ciobanu³

et al. 2020

PLoS ONE

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“…The glymphatic system is driven by cardiorespiratory brain pulsations that push CSF from the limitans externa of the BBB into the brain tissue and further drive soluble proteins into the perivascular space and away from the brain ( Mestre et al , 2018 b ). While some opposing views exist ( Smith et al , 2017 ; Abbott et al , 2018 ; Faghih and Sharp, 2018 ), researchers have found increasing evidence of a pulsation-driven glymphatic system ( Iliff and Nedergaard, 2013 ; Nedergaard, 2013 ; Xie et al , 2013 ; Iliff et al , 2015 , Mestre et al , 2018 a , b ; Rasmussen et al , 2018 ; Lilius et al , 2019 ; Mortensen et al , 2019 ). Importantly, a recent human study using focused BBB opening demonstrated a supra-diffusive glymphatic convection of MRI contrast media from the brain parenchyma ( Meng et al , 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Respiratory-related brain pulsations are increased in epilepsy—a two-centre functional MRI study

Kananen

Helakari

Korhonen

et al. 2020

Brain Communications

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Resting state functional MRI has shown potential for detecting changes in cerebral blood oxygen level-dependent signal in patients with epilepsy, even in the absence of epileptiform activity. Furthermore, it has been suggested that coefficient of variation mapping of fast functional MRI signal may provide a powerful tool for identification of intrinsic brain pulsations in neurological diseases such as dementia, stroke, and epilepsy. In this study, we used fast functional MRI sequence (magnetic resonance encephalography) to acquire ten whole brain images per second. We used the functional MRI data to compare physiological brain pulsations between healthy controls (n = 102) and patients with epilepsy (n = 33), and furthermore to drug-naïve seizure patients (n = 9). Analyses were performed by calculating coefficient of variation and spectral power in full-band and filtered sub-bands. Brain pulsations in the respiratory-related frequency sub-band (0.11–0.51 Hz) were significantly (p<0.05) increased in patients with epilepsy, with an increase in both signal variance and power. At the individual level, over 80% of medicated and drug-naïve seizure patients exhibited areas of abnormal brain signal power that correlated well with the known clinical diagnosis, while none of the controls showed signs of abnormality with the same threshold. The differences were most apparent in the basal brain structures, respiratory centers of brain stem, midbrain, and temporal lobes. Notably, full-band, very low frequency (0.01-0.1 Hz) and cardiovascular (0.8-1.76 Hz) brain pulses showed no differences between groups. This study extends and confirms our previous results of abnormal fast functional MRI signal variance in epilepsy patients. Only respiratory-related brain pulsations were clearly increased with no changes in either physiological cardiorespiratory rates or head motion between the subjects. The regional alterations in brain pulsations suggest that mechanisms driving the cerebrospinal fluid homeostasis may be altered in epilepsy. Magnetic resonance encephalography has both increased sensitivity and high specificity for detecting the increased brain pulsations, particularly in times when other tools for locating epileptogenic areas remain inconclusive.

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“…For instance, dexmedetomidine and ketamine enhance the CSF influx alongside perivascular spaces [50]. Moreover, similar to what happens during sleep, anesthesia is associated with a substantial increase in both perivascular and extracellular space volume [51]. Thus, the effects we have observed with TGN-20 induced under anesthesia might be peculiar to this this brain state and not necessarily be identical in awake animals.…”

Section: Discussionmentioning

confidence: 80%

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

Debacker¹,

Djemaï²,

Tsurugizawa³

et al. 2020

Preprint

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21The Glymphatic System (GS) has been proposed as a mechanism to clear brain tissue from waste. Its 22 dysfunction might lead to several brain pathologies, including the Alzheimer's disease. A key 23 component of the GS and brain tissue water circulation is the astrocyte which is regulated by 24 acquaporin4 (AQP4), a membrane-bound water channel on the astrocytic end-feet. Here we 25 investigated the potential of diffusion MRI to monitor astrocyte activity in a mouse brain model 26 through the inhibition of AQP4 channels with TGN-020. Upon TGN-020 injection, we observed a 27 significant decrease in the Sindex, a diffusion marker of tissue microstructure, and a significant increase 28 of the water diffusion coefficient (sADC) in cerebral cortex and hippocampus compared to saline 29 injection. These results indicate the suitability of diffusion MRI to monitor astrocytic activity in vivo 30 and non-invasively. 31

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Dexmedetomidine enhances glymphatic brain delivery of intrathecally administered drugs

Cited by 87 publications

References 44 publications

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

Respiratory-related brain pulsations are increased in epilepsy—a two-centre functional MRI study

Diffusion MRI reveals in vivo and non-invasively changes in astrocyte function induced by an aquaporin-4 inhibitor

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