WEBVTT 00:00:00.000 --> 00:00:05.457 Young Kwang Kim, Yun Jae Cha and colleagues published this study in Redox Biology 00:00:05.457 --> 00:00:10.623 in twenty twenty six. The animal work was carried out at Seoul National University in 00:00:10.623 --> 00:00:15.568 South Korea. They wanted to find out whether blocking an enzyme could protect the nerve 00:00:15.568 --> 00:00:21.223 cells damaged in Parkinson's. They tested this in mice and laboratory cells, and also 00:00:21.223 --> 00:00:24.938 examined human brain tissue donated after death. 00:00:25.750 --> 00:00:30.835 Parkinson's involves the loss of nerve cells that produce dopamine, a chemical involved 00:00:30.835 --> 00:00:36.443 in controlling movement. The researchers tested a drug called S W zero three 00:00:36.443 --> 00:00:41.853 three two nine one. It blocks 15-PGDH. This is an 00:00:41.853 --> 00:00:47.020 enzyme: a protein that helps chemical reactions happen. The question was whether 00:00:47.020 --> 00:00:51.850 blocking it would reduce damage and preserve movement. In the following experiments, 00:00:51.850 --> 00:00:55.146 the drug was started before the experimental injury. 00:00:55.958 --> 00:01:00.799 The team compared donated brain tissue from people with Parkinson's with tissue from 00:01:00.799 --> 00:01:06.430 comparison subjects. They examined the substantia nigra, the brain region containing 00:01:06.430 --> 00:01:11.748 the dopamine-producing cells affected by Parkinson's. There were five to eight samples 00:01:11.748 --> 00:01:17.158 per group. They measured messenger R N A: instructions cells use to make 00:01:17.158 --> 00:01:23.090 proteins. Instructions for making this enzyme were higher in the Parkinson's samples. 00:01:23.090 --> 00:01:27.212 This comparison measured a difference; it did not test a treatment. 00:01:28.042 --> 00:01:33.499 For the first mouse experiment, the team used MPTP, a toxin that damages 00:01:33.499 --> 00:01:38.665 dopamine-producing nerve cells. There were three kinds of comparison: mice without 00:01:38.665 --> 00:01:44.087 toxin exposure; mice given the toxin and the drug's carrier liquid; and mice 00:01:44.087 --> 00:01:49.033 given the toxin plus the active drug. The carrier is the liquid used to deliver the 00:01:49.033 --> 00:01:54.710 drug. Comparing the last two shows what changes when the active drug is added. 00:01:54.710 --> 00:01:57.810 The treated mice received one of two doses. 00:01:58.625 --> 00:02:03.594 First, the mice had one week to adjust to their surroundings. Next came two days of 00:02:03.594 --> 00:02:08.366 drug treatment before any toxin was given. The drug was injected into the abdominal 00:02:08.366 --> 00:02:14.090 cavity twice a day. The two doses were zero point five and five milligrams per kilogram 00:02:14.090 --> 00:02:19.535 of body weight. That unit adjusts the amount of drug for the animal's weight. These are 00:02:19.535 --> 00:02:22.309 the doses used in the mouse experiment. 00:02:23.125 --> 00:02:28.489 The mice then received the toxin once a day for seven days. The toxin dose was thirty 00:02:28.489 --> 00:02:33.957 milligrams per kilogram. Drug treatment continued alongside it. Finally, two 00:02:33.957 --> 00:02:39.403 to three hours after the last toxin injection, the researchers tested movement. The 00:02:39.403 --> 00:02:45.045 order matters: the drug was already being given when injury began. This experiment 00:02:45.045 --> 00:02:49.654 tested protection during toxin exposure, rather than starting treatment after 00:02:49.654 --> 00:02:51.500 Parkinson's had developed. 00:02:52.333 --> 00:02:57.859 They used three movement tests, with ten to eleven mice per group. In the rotating-rod 00:02:57.859 --> 00:03:02.608 test, they measured how long a mouse stayed on a turning rod before falling. They 00:03:02.608 --> 00:03:08.122 scored hind-limb clasping: how much the back legs drew together. In the pole test, 00:03:08.122 --> 00:03:13.208 they measured how long the mouse took to turn downward and descend. Better performance 00:03:13.208 --> 00:03:18.154 meant longer on the rod, less clasping, and shorter times on the pole. 00:03:18.958 --> 00:03:24.113 The toxin worsened all three movement measures. Mice receiving the drug had less 00:03:24.113 --> 00:03:29.314 impairment, with stronger protection at the higher dose. The researchers describe the 00:03:29.314 --> 00:03:34.759 result as, preserving motor performance to near non MPTP exposed 00:03:34.759 --> 00:03:39.972 levels. In plain language, the treated mice performed close to mice that had not 00:03:39.972 --> 00:03:45.661 received the toxin. That was a positive result for protection in this experiment. 00:03:46.500 --> 00:03:52.050 The team also examined brain tissue using a protein called tyrosine hydroxylase 00:03:52.050 --> 00:03:57.448 as a marker of dopamine-producing nerve cells. They used staining to locate and measure 00:03:57.448 --> 00:04:02.917 this marker. Toxin exposure reduced the staining signal. The drug preserved 00:04:02.917 --> 00:04:08.489 it, with greater protection at the higher dose. The toxin-model staining comparison 00:04:08.489 --> 00:04:14.364 used four mice per group. This tissue measurement supported the movement findings. 00:04:15.167 --> 00:04:19.962 In a separate experiment, the researchers compared mice with one copy of the enzyme's 00:04:19.962 --> 00:04:26.162 gene removed with their littermates. A gene contains instructions for making a protein. 00:04:26.162 --> 00:04:31.270 Removing one copy reduced the enzyme genetically, without using the drug. 00:04:31.270 --> 00:04:36.739 Eight-week-old male and female mice received toxin daily for seven days, followed 00:04:36.739 --> 00:04:42.067 by movement tests two to three hours later. The genetically altered mice were better 00:04:42.067 --> 00:04:47.442 protected. Movement tests used fifteen to twenty two mice per group. 00:04:48.250 --> 00:04:54.229 The team also used LPS, a bacterial substance that triggers inflammation. 00:04:54.229 --> 00:04:59.338 Mice received drug or carrier before LPS was injected into both sides of the 00:04:59.338 --> 00:05:04.968 substantia nigra. Drug treatment continued at five milligrams per kilogram, twice 00:05:04.968 --> 00:05:10.529 daily. One week later, the team used the same movement tests. The drug prevented 00:05:10.529 --> 00:05:15.580 the movement deficits seen with LPS. This tested a different way of injuring the 00:05:15.580 --> 00:05:17.879 brain from the toxin experiment. 00:05:18.708 --> 00:05:24.176 A further experiment used alpha synuclein, a protein that can form abnormal clumps in 00:05:24.176 --> 00:05:29.656 Parkinson's. Seven-week-old mice had one week to acclimate, followed by two days of 00:05:29.656 --> 00:05:35.031 drug or carrier before surgery. The researchers used a viral delivery system to 00:05:35.031 --> 00:05:39.873 increase production of this protein in the brain, then injected prepared protein 00:05:39.873 --> 00:05:44.981 clumps. They assessed movement and collected brain tissue thirty three days after 00:05:44.981 --> 00:05:50.334 injection. The drug dose was five milligrams per kilogram, twice daily. 00:05:51.167 --> 00:05:55.648 The drug protected movement and preserved the nerve-cell staining marker in this model 00:05:55.648 --> 00:06:01.163 too. These measurements used five to six mice per group. Markers of chemical 00:06:01.163 --> 00:06:06.062 damage were also lower. However, the measured buildup of an abnormal form of alpha 00:06:06.062 --> 00:06:11.542 synuclein did not significantly decrease. So the positive result was protection 00:06:11.542 --> 00:06:16.383 of movement and tissue markers. The study did not demonstrate that the drug cleared 00:06:16.383 --> 00:06:18.380 this protein buildup. 00:06:19.208 --> 00:06:24.200 To investigate why the drug helped, the team compared gene activity in brain tissue 00:06:24.200 --> 00:06:29.715 from drug-treated and carrier-treated mice. They used R N A sequencing, which 00:06:29.715 --> 00:06:34.731 reads the messages made from many genes at once. The results pointed toward reduced 00:06:34.731 --> 00:06:40.130 inflammation and reduced production of damaging reactive chemicals. Some individual 00:06:40.130 --> 00:06:45.331 gene results did not pass the stricter statistical check used when testing many genes 00:06:45.331 --> 00:06:50.707 together. The researchers therefore tested candidate changes in new, independent groups 00:06:50.707 --> 00:06:51.995 of animals. 00:06:52.833 --> 00:06:58.638 Follow-up tissue tests found lower markers of chemical damage with enzyme inhibition. 00:06:58.638 --> 00:07:03.688 The researchers also examined the blood-brain barrier: the blood-vessel boundary that 00:07:03.688 --> 00:07:09.191 controls passage into brain tissue. Using an electron microscope, they saw less 00:07:09.191 --> 00:07:14.590 structural damage in drug-treated mice exposed to the toxin. They also measured a blood 00:07:14.590 --> 00:07:19.733 antibody in the brain as a sign of leakage. The drug prevented the toxin-related 00:07:19.733 --> 00:07:21.998 increase in that leakage marker. 00:07:22.833 --> 00:07:28.522 The team then examined microglia, the brain's immune cells, grown in the laboratory. 00:07:28.522 --> 00:07:33.921 They added prostaglandin E two, a chemical signal normally broken down by the enzyme, 00:07:33.921 --> 00:07:39.412 before exposing the cells to LPS. This reduced inflammatory and reactive-chemical 00:07:39.412 --> 00:07:45.310 responses. One result was less lipocalin two, a protein linked to nerve-cell 00:07:45.310 --> 00:07:50.801 damage. Blocking EP4, a receptor that receives the chemical signal, interfered 00:07:50.801 --> 00:07:55.573 with that effect. These tests help explain a possible pathway. 00:07:56.375 --> 00:08:01.530 The main result was positive: blocking this enzyme protected movement and nerve-cell 00:08:01.530 --> 00:08:06.998 markers across three mouse injury models. Reducing the enzyme genetically supported 00:08:06.998 --> 00:08:12.803 the result in the toxin model. But the treatment began before the experimental injury. 00:08:12.803 --> 00:08:17.831 The human tissue comparison was not a treatment trial. This paper therefore supports 00:08:17.831 --> 00:08:22.556 further testing of the target; it does not establish that the drug treats Parkinson's 00:08:22.556 --> 00:08:27.258 in people. The protein buildup measurement also remained unresolved. 00:08:28.083 --> 00:08:32.286 The authors call for further experiments to test the chemical pathway in living 00:08:32.286 --> 00:08:37.917 animals, including blocking specific parts of it. They also call for additional human 00:08:37.917 --> 00:08:43.536 tissue samples. These are the next steps proposed in this publication. The result 00:08:43.536 --> 00:08:49.562 to take from this study is specific: reducing the activity of 15-PGDH 00:08:49.562 --> 00:08:54.728 protected mice against several experimental injuries. Further work is needed to find 00:08:54.728 --> 00:08:58.501 out how that protection might apply to Parkinson's treatment.