Review of Research on the Treatment Potential for Cognitive Deficits in Traumatic Brain Injury

Research Background

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. In Europe, the annual incidence of TBI is at least 4 million cases, imposing a heavy burden on patients, society, and health systems, yet the available treatment options remain limited. After TBI, activation of the complement system triggers an inflammatory response, exacerbating brain damage, leading to tissue injury and loss of neurological function. Activation of specific enzymes mascps (mannose-binding lectin-associated serine proteases) in the lectin pathway (LP) of the complement system, and elevated levels of LP effector enzyme masp-2 in serum and brain, are associated with the severity of tissue damage and poorer prognosis in TBI patients. The authors conducted a preliminary study to test the effect of an inhibitory masp-2 antibody (α-masp-2) and found that administration can alleviate sensorimotor and cognitive deficits in a mouse model. Additionally, previous studies have indicated the crucial role of masp-1 in LP activation, prompting the authors to conduct further research to evaluate the inhibitory masp-1 antibody (α-masp-1).

Research Source

The paper was written by Domenico Mercurio and Francesca Pischiutta, among others, and was published in the Journal of Neuroinflammation from the Istituto di Ricerche Farmacologiche Mario Negri IRCCS in Milan, Italy, in 2024. Elisa R. Zanier and Stefano Fumagalli are the corresponding authors.

Research Process

The study used a controlled cortical impact (CCI) model in mice to evaluate the effect of α-masp-2 and α-masp-1 treatment on improving cognitive deficits after TBI. A total of 78 mice were used in the study, and they received intraperitoneal injections of α-masp-2, α-masp-1, or isotype control antibodies at 4 hours and 24 hours following TBI or sham surgery. Cognitive deficits were assessed using tests such as the Barnes Maze, while the extent of damage was evaluated histologically, and systemic LP activity was measured.

Main Research Findings

• Mice treated with α-masp-2 showed a reduction in sensorimotor and cognitive deficits within 5 weeks after TBI.
• Compared to the control antibody group, the α-masp-2 treated group demonstrated significant improvement in the Barnes Maze test.
• Treatment was correlated with health scores, which combined results from behavioral tests, showing that α-masp-2 provided the best protective effect.
• Histological analysis found that mice treated with α-masp-2 had reduced injury volumes, although no significant differences in neuron loss were observed.

Research Conclusion and Value

The study concluded that inhibiting the LP effector enzyme masp-2 is a promising strategy for treating TBI, capable of limiting neurological deficits and tissue loss. This strategy has clinical application value because an antibody against masp-2 has already completed multiple late-stage clinical trials for other indications. Moreover, this research highlights the potential impact of initiating interventions within a clinically relevant time window following TBI on the recovery process.

Research Highlights

• Treatment with α-masp-2 demonstrated high safety and efficacy, revealing a new direction for interventions following TBI.
• The rigorously designed intervention protocol and detailed data analysis confirmed the role of specific complement pathway molecules in the TBI process.
• The study used clinically relevant treatment time points, indicating good translational potential and possibly leading to new treatments that could change clinical practices.