3,6'-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation.
Chih-Tung LinDaniela LeccaLing-Yu YangWeiming LuoMichael T ScerbaDavid TweediePen-Sen HuangYoo-Jin JungDong Seok KimChih-Hao YangBarry J HofferJia-Yi WangNigel H GreigPublished in: eLife (2020)
Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6'-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.
Keyphrases
- traumatic brain injury
- oxidative stress
- cell death
- diabetic rats
- brain injury
- severe traumatic brain injury
- high glucose
- lipopolysaccharide induced
- drug induced
- lps induced
- inflammatory response
- neuropathic pain
- signaling pathway
- type diabetes
- endoplasmic reticulum stress
- multiple sclerosis
- induced apoptosis
- liver failure
- cardiovascular events
- multiple myeloma
- endothelial cells
- spinal cord injury
- heat stress
- cardiovascular disease
- coronary artery disease
- functional connectivity
- mild traumatic brain injury