Page 101 - NNS 2014 Abstract Book

1

The Ohio State University, Columbus, USA

2

University of Arizona, Phoenix, USA

Traumatic brain injury (TBI) is associated with cerebral edema,

blood brain barrier breakdown and neuroinflammation that contrib-

ute to the degree of injury severity and functional recovery. Un-

fortunately, there are no effective pro-active interventions for

limiting immediate or long-term neurological consequences after

TBI. Therefore, the objective of this study was to determine the

efficacy of methylene blue, an anti-oxidant agent, to reduce in-

flammation and behavioral complications associated with a diffuse

brain injury. Here, we show that immediate methylene blue infusion

(i.v., 30 minutes after TBI) reduced neuroinflammation, microglial

activation, and improved behavioral recovery after midline fluid

percussion injury in mice. Specifically, edema and inflammatory

gene expression in the hippocampus after TBI were significantly

reduced by MB 1 day post injury (dpi). Moreover, MB intervention

attenuated TBI-induced inflammatory gene expression (IL-1

b

, TNF-

a

) in enriched microglia/macrophages 1 dpi. Cell culture experi-

ments confirmed that MB treatment directly reversed activation of

BV2 microglia by lipopolysaccharide (LPS). For example, MB in-

tervention reduced IL-1

b

and increased IL-10 mRNA levels in LPS-

activated BV2 microglia. Next, functional recovery was determined

in mice after TBI and MB intervention. MB intervention after TBI

did not prevent reductions in body weight and motor coordination 1–

7 dpi. Nonetheless, MB attenuated the development of acute de-

pressive-like behavior after TBI (7 dpi). Taken together, our data

shows that immediate intervention with MB was effective in re-

ducing neuroinflammation and improving behavioral recovery after

TBI. Thus, MB intervention may reduce life-threatening complica-

tions of TBI, including edema and neuroinflammation, and protect

against the development of neuropsychiatric deficits.

Key words

depression, methylene blue, neuroinflammation, TBI

D1-02

DELAYED METHYLENE BLUE IMPROVES LESION VO-

LUME AND BEHAVIORAL OUTCOME FOLLOWING TBI

Watts, L.T.

, Long, J.A., Chemello, J., Shen, Q., Duong, T.Q.

University of Texas Health Science Center, San Antonio, US

Methylene blue (MB) has unique energy-enhancing and antioxidant

properties and has positive acute therapeutic effects following TBI in

rats. We hypothesized that delayed MB treatment would reduce le-

sion volume and improve functional recovery in a rat TBI model.

Anesthetized rats underwent a 6mm craniotomy over the left primary

motor/somatosensory cortex region to expose the dura matter and

were impacted using a pneumatic cortical impactor (impact velocity

5.0 m/s, 250

l

s dwell time, and 1mm depth) to mimic a moderate

TBI. One hour or twenty-four hours after TBI, animals received

intravenous infusion of saline (vehicle) or MB (1 mg/kg). MRI was

utilized to longitudinally monitor T

2

on days 0, 2, 7, and 14 after

TBI. Comparisons of MRI scans were made with the progression of

lesion volume, behavioral analysis (cylinder test and foot fault test)

(days 0, 2 7, and 14), and histology (day 14). Vehicle-treated animals

initial lesion volume grew larger by 92% and peaked in size on day

2. By contrast, the one and twenty four hour MB-treated groups

lesion volume growth was smaller on day 2 compared to the vehicle-

treated group by 21% and 23%, respectively (P

<

0.05). Lesion

volume in MB treated rats continued to significantly decrease in

lesion volume compared to vehicle-treated rats on days 7 and 14

post-injury (P

<

0.05). Immunohistochemistry confirmed final lesion

volumes upon sacrifice on day 14. The behavioral tests demonstrated

impairment of motor function of vehicle- and MB-treated rats on

days 0 and 2 (P

<

0.05). However, MB treated rats demonstrated

improved motor function by day 7 compared to vehicle treated rats,

indicative of improved neurological status. In summary, MB mark-

edly reduces lesion size and improves behavioral outcome even

when delivered 24 hours post TBI. Delayed treatment would enable

increased therapeutic benefits to larger patient population. These

results suggest that restoration of mitochondrial function and mini-

mizing reactive oxygen species production is a promising neuro-

protective strategy in TBI.

Key words

methylene blue, MRI, traumatic brain injury

D1-03

HYPOTHERMIA IN TBI FOR CONTROL OF INTRA-

CRANIAL HYPERTENSION AS THERAPEUTIC OPTION:

ICP TRENDS AND GRADED HYPOTHERMIA

Gupta, D.K.

1

, Andrews, P.

2

, Bindra, A.

1

, Tiwari, P.

1

, Singh, P.

1

,

Sharma, B.S.

1

Department of Neurosurgery, All India Institute of Medical Sciences,

New Delhi, India

2

Department of Anaesthesia, University of Cambridge, Cambridge,

UK

Hypothermia has the potential to influence key destructive mechanism

following traumatic brain injury(TBI), reduces intracranial pressure

and possibly provides neuroprotection. The present study will test to

titrated hypothermia for ICP reduction after TBI. The hypothesis is

that therapeutic hypothermia will reduce morbidity/mortality com-

pared to those receiving standard care alone after TBI.

This is prospective RCT to examine effects of hypothermia (32–

35 C) on raised ICP after TBI. Adults with primary closed TBI with

raised ICP

>

20 mm Hg for

‡

30 minutes after first line treatments and

with no obvious reversible cause and with abnormal CT scan are

randomized to hypothermia (32–35 C)/normothermia group. Hy-

pothermia initiated with refrigerated 0.9% saline/maintained using

surface cooling blanket. Depth of hypothermia guided by ICP with a

higher pressure level warranting a cooler target temperature. Ther-

apeutic hypothermia is maintained for at least 48 hours in treatment

group but if there is inadequate response to hypothermia patients are

taken up for decompressive craniectomy. Outcome in this abstract is

assessed on ICP control, length of stay in ICU and hospital stay.

The result is than 28 patients (13 in hypothermia group, 15 in

control group), mean age was 35.3 yrs, (and range 16–50 yrs, 27

males, mean ICP at randomization was 22.6 and 24 mm Hg in hy-

pothermia and control group respectively. CT Marshall grade 6 was

observed in 18/28 cases (traumatic SAH in 16, acute subdural he-

matomas in 11 cases).There were no coagulation abnormalities in

either group. Mean duration of ICU and hospital stay was 10.2 days/

9.5 days and 19.5/18.6 days in normothermia and hypothermia group

respectively. Admission was longer in the control group but was not

statistically significant.

The conclusion is that Hypothermia can be used safely as an ad-

junct to other modalities for controlling ICP in severe TBI. It is not

associated with a longer duration of ICU/hospital stay or other com-

plications when compared with controls.

Key words

hypothermia, raised intracranial pressure, traumatic brain injury

A-101