The salutary effects of DHA dietary supplementation on cognition, neuroplasticity, and membrane homeostasis after brain trauma

Abstract

The pathology of traumatic brain injury (TBI) is characterized by the decreased capacity of neurons to metabolize energy and sustain synaptic function, likely resulting in cognitive and emotional disorders. Based on the broad nature of the pathology, we have assessed the potential of the omega-3 fatty acid docosahexaenoic acid (DHA) to counteract the effects of concussive injury on important aspects of neuronal function and cognition. Fluid percussion injury (FPI) or sham injury was performed, and rats were then maintained on a diet high in DHA (1.2% DHA) for 12 days. We found that DHA supplementation, which elevates brain DHA content, normalized levels of brain-derived neurotrophic factor (BDNF), synapsin I (Syn-1), cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII), and improved learning ability in FPI rats. It is known that BDNF facilitates synaptic transmission and learning ability by modulating Syn-I, CREB, and CaMKII signaling. The DHA diet also counteracted the FPI-reduced manganese superoxide dismutase (SOD) and Sir2 (a NAD+-dependent deacetylase). Given the involvement of SOD and Sir2 in promoting metabolic homeostasis, DHA may help the injured brain by providing resistance to oxidative stress. Furthermore, DHA normalized levels of calcium-independent phospholipase A2 (iPLA2) and syntaxin-3, which may help preserve membrane homeostasis and function after FPI. The overall results emphasize the potential of dietary DHA to counteract broad and fundamental aspects of TBI pathology that may translate into preserved cognitive capacity.

Figures

FIG. 1.

Docosahexaenoic acid (DHA) supplementation provides protection against cognitive disability in fluid-percussion-injured (FPI) rats. Learning performance was scored as average escape latency to locate the platform in the Morris water maze. The escape latencies were longer in FPI rats compared to sham animals. FPI rats receiving DHA supplementation had lower latencies than untreated FPI rats (on days 4 and 5; RD, regular diet).

FIG. 2.

Effects of docosahexaenoic acid (DHA) supplementation on brain-derived neurotrophic factor (BDNF; A) and calcium/calmodulin-dependent kinase II (CaMKII; B) levels in the hippocampus of fluid-percussion-injured (FPI) rats. FPI resulted in reductions of BDNF and CaMKII. DHA increased levels of both in FPI rats compared to untreated FPI rats. The values were converted to percentages of RD-sham animals (mean±standard error of the mean; *p<0.05 versus RD-sham; #p<0.05 versus untreated FPI animals; RD, regular diet).

FIG. 3.

Effects of docosahexaenoic acid (DHA) supplementation on synapsin I (Syn-I, A) and cAMP-responsive element-binding protein (CREB; B) levels in the hippocampi of fluid-percussion-injured (FPI) rats. FPI resulted in reductions in Syn-I and CREB. DHA supplementation increased Syn-I and CREB levels in FPI rats compared to untreated FPI rats. The values were converted to percentages of RD-sham animals (mean±standard error of the mean; *p<0.05 versus RD-sham animals; #p<0.05 versus untreated FPI animals; RD, regular diet).

FIG. 4.

Effects of docosahexaenoic acid (DHA) supplementation on 4-hydroxynonenal (4-HNE) levels in the hippocampus of fluid-percussion-injured (FPI) rats. (A) FPI resulted in an increase in 4-HNE. DHA supplementation reduced 4-HNE levels in FPI rats compared to untreated FPI rats. The values were converted to percentages of RD-sham animals (mean±standard error of the mean; *p<0.05 versus RD-sham animals; #p<0.05 versus untreated FPI animals; RD, regular diet). (B) Correlation analysis between 4-HNE and latency of the last day of testing in the Morris water maze. Each dot represents a single animal.

FIG. 5.

Effects of docosahexaenoic acid (DHA) supplementation on superoxide dismutase (SOD; A) and Sir2 (B) levels in the hippocampi of fluid-percussion-injured (FPI) rats. FPI resulted in reductions of SOD and Sir2. DHA supplementation increased SOD and Sir2 in FPI rats compared to untreated FPI rats. The values were converted to percentages of RD-sham animals (mean±standard error of the mean; *p<0.05 versus RD-sham animals; #p<0.05 versus untreated FPI animals; RD, regular diet).

FIG. 6.

Effects of docosahexaenoic acid (DHA) supplementation on calcium-independent phospholipase A2 (iPLA2; A) and syntaxin-3 (STX-3; B) levels in the hippocampi of fluid-percussion-injured (FPI) rats. FPI resulted in reductions of iPLA2 and STX-3. DHA supplementation increased levels of both in FPI rats compared to untreated FPI rats. The values were converted to percentages of RD-sham animals (mean±standard error of the mean; *p<0.05 versus RD-sham animals; #p<0.05 versus untreated FPI animals; RD, regular diet).

FIG. 7.

Possible mechanisms underlying the beneficial effects of docosahexaenoic acid (DHA) dietary supplementation on the injured brain. Sir2 and its induced superoxide dismutase (SOD) may provide protection against insults to the brain, and therefore a reduction of Sir2 and subsequently SOD levels as a consequence of brain injury may reduce its resistance to insults. In turn, dietary supplementation with DHA may protect the brain from trauma by maintaining levels of Sir2 and the antioxidant SOD. Sir2 may provide neuroprotection via mechanisms that promote stress resistance, such as induction of antioxidant gene expression and maintenance of energy homeostasis. Brain-derived neurotrophic factor (BDNF), its downstream effectors synapsin I (Syn-I) and cAMP-responsive element-binding protein (CREB), and calcium/calmodulin-dependent kinase II (CaMKII) play important roles in synaptic plasticity. Reductions of these molecules may result in synaptic dysfunction and subsequent cognitive impairment. Compensation for those reductions via DHA supplementation can reduce the dysfunction of plasticity, thereby leading to cognitive improvement.