A small study in rats found that losartan was associated with less structural and cellular damage in the cerebellum after exposure to carbon tetrachloride, a chemical used experimentally to produce injury. A nanoparticle version performed better than regular losartan on several laboratory measures, although the study did not show whether either treatment improved movement, balance or coordination.
The experiment involved 24 adult male Sprague-Dawley rats divided into four groups of six. Three groups received carbon tetrachloride injections twice a week for six weeks. Two of those groups then received four weeks of oral losartan, either in its regular form or as nanoparticles. Treatment began after the injury phase, so the researchers were testing an intervention after damage had occurred.
What the researchers measured
At week 10, the investigators examined cerebellar tissue, oxidative-stress markers, messenger RNA levels and protein staining. The people scoring the tissue slides did not know which group each slide came from.
Carbon tetrachloride exposure was linked with fewer Purkinje cells, a thinner granular layer and weaker myelin staining than in untreated control rats. It also lowered glutathione, catalase and superoxide dismutase, which are measures related to antioxidant defenses, while increasing malondialdehyde, a marker of oxidative stress.
Both forms of losartan were associated with improvement compared with untreated toxin-exposed rats. Purkinje cell counts averaged 5.0 per microscope field in the untreated toxin group, compared with 7.6 with regular losartan and 10.0 with nanoparticle losartan. The difference between the two treatment groups was not statistically significant for this measure.
Granular-layer thickness was 188 micrometers in the untreated toxin group, 225 micrometers with regular losartan and 235 micrometers with nanoparticles, compared with 236 micrometers in controls. Myelin staining measured 54.4, 60.5 and 69.5, respectively, compared with 75.7 in controls.
Where nanoparticles appeared stronger
Nanoparticle losartan performed significantly better than regular losartan on several measures, including lower malondialdehyde, improved antioxidant measures, myelin staining and staining related to RIPK1, RIPK3, caspase-8, GFAP and Iba1.
For example, RIPK1-stained area was 1.2% with nanoparticle losartan and 3.2% with regular losartan. RIPK3-stained area was 5.5% and 9.5%, respectively. Messenger RNA levels for Tnf, Ripk1 and Ripk3 fell to similar levels with both forms; Ripk3 was 1.15 with each treatment. Mlkl gene activity fell further with regular losartan than with nanoparticles, reaching 0.33 versus 1.16.
The nanoparticle preparation consisted of pure losartan ground into tiny crystals in a ball mill, without added carriers or coatings. An electron microscope was used to confirm the particles’ shape. However, the study did not measure particle-size distribution, stability, blood or brain drug levels, or how the crystals behaved in the body. The researchers described the nanoparticle advantage as an observation, not proof that the formulation was absorbed better or acted through a different mechanism.
Why the cell-death findings remain uncertain
The study focused partly on necroptosis, a form of regulated cell death involving RIPK1, RIPK3 and MLKL. Caspase-8 can act as a brake on this sequence. In the untreated toxin group, RIPK3 staining covered 14.8% of the stained area, while GFAP and Iba1 staining measured 20.8% and 16.9%. The study found lower values for several of these markers after treatment.
Those findings indicate changes associated with necroptosis-related signaling, but they do not prove that necroptosis was activated or blocked. The researchers did not measure activated, phosphorylated RIPK3 or MLKL. Protein findings were also based on stained tissue area rather than direct protein measurements such as Western blots.
What this study cannot show
The experiment did not assess behavior, movement, balance or coordination. It also did not examine the rats at the end of the six-week injury period, so it cannot show how much damage was reversed from a baseline. Instead, the week-10 results compare treated animals with untreated toxin-exposed animals.
There was no healthy group receiving losartan alone and no sham-milled comparison group. With only six male rats per group, one toxin and one dose, the experiment is an early animal study. The findings cannot establish that losartan benefits people, protects human brain function or should be used for toxin-related injury.
Losartan is a blood-pressure drug that blocks the AT1 receptor for angiotensin II. It is prescribed for blood pressure and kidney protection, not for brain injury or toxin exposure. The nanoparticle preparation in this experiment was an experimental laboratory formulation.
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